MET is a RTK expressed mainly in epithelial cells and activated by its high-affinity ligand, hepatocyte growth factor (HGF). MET activation by HGF promotes a program known as invasive growth, comprising cell division, cell motility, extracellular matrix digestion, invasion, survival, and morphogenic differentiation (Bardelli et al., 1997a; Tamagnone and Comoglio, 1997; Rubin et al., 1993). In an organism, the MET/HGF pair is involved in many processes, including embryonic development (Bladt et al., 1995; Schmidt et al., 1995; Uehara et al., 1995; Maina et al., 1996), development of specific organs/tissues such as the placenta, liver, lung, and muscle (Bladt et al., 1995; Schmidt et al., 1995; Woolf et al., 1995; Yang et al., 1995), and tissue regeneration (Matsumoto and Nakamura, 1992).

MET is synthesized as a precursor which matures through proteolytic cleavage. This leads to the formation of a heterodimeric receptor composed of an extracellular part, containing a SEMA domain, a PSI domain, and four immunoglobulin plexin transcription factor (IPT) domains, and an intracellular part, containing a juxtamembrane domain (JM), a tyrosine kinase domain (TKD), and a C-terminal tail (Figure 1; Stella and Comoglio, 1999; Fernandes et al., 2019; Montagne et al., 2014).

Figure 1

Download asset Open asset

HGF, the high-affinity ligand of MET, is a 90 kDa heterodimeric protein composed of an α subunit with an N domain and four loop domains (domains k1 to k4) and a β chain displaying homology to a serine protease domain (SPH) but lacking catalytic activity (Gherardi et al., 2003). The HGF/MET interaction is ensured by binding the SPH and k1 domains of HGF to the SEMA domain of MET (Gherardi et al., 2006; Uchikawa et al., 2021). However, HGF/MET cryo-EM structure resolutions allow the proposing of different scenarios for MET dimerization. First, MET dimerization could be ensured by HGF dimerization via a top-to-tail interaction of N and k1. This would lead to the association of two MET receptors, each interacting with an HGF. This 2:2 model of interaction suggests a symmetric HGF/MET structure (Gherardi et al., 2006). Second, in a recent study, it has been proposed that one HGF can bind two MET receptors, one through the SPH domain and one through the k1 domain, this leading to MET dimerization. This asymmetric 2:1 model could be further stabilized by heparin and/or binding of a second HGF to the second MET receptor (Uchikawa et al., 2021).

Once the MET receptor interacts with its ligand, it undergoes phosphorylation on two residues of the catalytic domain (Y1252/Y1253 or Y1234/Y1235 in the short MET isoform). It is worth noting that all the mentioned amino acid positions are annotated from the long isoform of MET (MET transcript variant 1 NM_001127500.3). The positions of some amino acids are also mentioned on the basis of the short isoform, as a reminder of the initial publication. Subsequently, other residues outside the catalytic domain are phosphorylated, including residue Y1367/Y1374 (Y1349/Y1356 in the short isoform) in the C-terminal tail, called the multi-substrate docking site (Longati et al., 1994; Ponzetto et al., 1994), as phosphorylated tyrosines in the C-terminal tail are able to recruit multiple effectors such as GRB2-associated binder-1 (GAB1), growth factor receptor–bound protein-2 (GRB2), SRC homology 2 domain-containing (SHC), phosphoinositide 3 kinase (PI3K), non-receptor tyrosine kinase SRC, signal transducer and activator of transcription 3 (STAT3), and phospholipase C-gamma (PLCγ). This multisubstrate docking site plays a key role in the induction by MET of intracellular signalling pathways and biological responses including survival, motility, invasion, and cell cycle progression (Figure 1; Ponzetto et al., 1993; Chiara et al., 2003; Rhoades Smith and Bilen, 2019). In parallel, MET signalling is downregulated by the juxtamembrane region of the cytoplasmic part of the receptor, encoded by exon 14 with its phosphorylated Tyr1021 (Tyr1003 in the short MET isoform) (Cortot et al., 2017).

To date, four main genomic events have been described that lead to MET activation and oncogene-driven tumorigenesis (Duplaquet et al., 2018). First, MET gene amplification or copy number gain (CNG), leading to MET overexpression and its ligand-independent activation, has been identified as responsible for carcinogenesis in several tumour types including glioblastoma (Cancer Genome Atlas Research Network, 2023), lung adenocarcinoma (LUAD) (Collisson et al., 2014), gastric cancer (GC) (Asaoka et al., 2010), colorectal cancer (CRC) (Umeki et al., 1999), and medulloblastoma (Tong et al., 2004). The phenomenon was observed for the first time in gastric carcinoma, where MET overexpression caused by gene amplification led to its activation and to the transformation of several cell lines (Ponzetto et al., 1991). Second, HGF overexpression has been observed in breast, gastric, colon, and lung cancers and leads to aberrant MET activation through establishment of an autocrine loop (Ujiie et al., 2012). The third mechanism, found in a limited number of tumours, is chromosomal rearrangement leading to MET fusion with another gene. This leads notably to constitutive MET activation or overexpression and involves fusions including KIF5B-MET in LUAD and BAIAP2L1-MET and C8ORF34-MET in RCC (Stransky et al., 2014). The fourth type of genomic event responsible for MET activation is MET-activating mutations, which constitute the main focus of this review. Since the first MET mutation was discovered in HPRC in 1997 (Schmidt et al., 1997), many MET mutations have been identified. The majority of MET mutations were found in papillary renal cancer and are located in the tyrosine kinase domain of MET. Over the last decade, however, other mutations have been identified outside the kinase domain. In NSCLC, for instance, missense mutations have been found in the SEMA and JM domains, in addition to a large panel of mutations leading to exon 14 skipping (Tovar and Graveel, 2017; Ma et al., 2005; Ma et al., 2003; Krishnaswamy et al., 2009; Schrock et al., 2016; Figure 1 and Table 1). Despite all the MET mutations already identified, novel MET mutations are constantly being discovered (Sebai et al., 2022).

Despite the numerous deregulations described previously, no direct causal link between MET and cancer progression was evidenced until 1997, when MET-activating mutations were found in HPRC and associated with cancer progression (Schmidt et al., 1997). Renal cell carcinoma is the most common type of kidney cancer in adults. It is a heterogeneous disease composed of multiple subtypes, such as clear cell renal cell carcinoma (80% of RCCs) and non-clear cell renal cell carcinoma, of which the most common subtype is papillary renal cell carcinoma (15–20% of RCCs). Papillary renal cell carcinoma (PRCC) is divided into two subtypes: type I and II, distinguished histologically, type II being the hereditary form (Rhoades Smith and Bilen, 2019; Mendhiratta et al., 2021; Akhtar et al., 2019). Interestingly, HPRC is the first cancer in which MET mutations, segregating from generation to generation, were identified as causal. The first direct link between MET mutations and cancer development was established in 1997 through genomic polymorphism analysis by Schmidt et al., who found the disease to segregate with a locus on chromosome 7q, carrying the MET proto-oncogene. Chromosome-7 duplication, rather than the loss at this location, suggested the involvement of an oncogene suspected of being MET (Schmidt et al., 1997). In addition, because MET belongs to the same family (the receptor tyrosine kinase family) as RET, a proto-oncogene already known to be mutated in other inherited cancer syndromes (Cortot et al., 2017), the MET proto-oncogene was sequenced rather than the two other genes also found at this locus. Through analysis of nine families affected by papillary renal carcinoma and sporadic papillary renal carcinoma, missense mutations of MET were identified, all located in the kinase domain, among which germline mutations (M1149T, V1206L, V1238I, D1246N, and Y1248C) and somatic mutations (D1246H, Y1228C, and M1268T) (Schmidt et al., 1997; Schmidt et al., 1999).

Following this initial identification, several functional studies were performed. Biochemical and biological assays on murine fibroblasts transfected with MET cDNA demonstrated an increase in MET autophosphorylation when mutations were inserted, demonstrating that these are able to cause constitutive activity of the MET receptor (Tovar and Graveel, 2017; Bardelli et al., 1997b; Jeffers et al., 1997; Bardelli et al., 1998; Graveel et al., 2004; Michieli et al., 1999). Interestingly, different levels of tyrosine kinase activity were observed according to the mutation (Jeffers et al., 1998), M1268T substitutions being identified as the most active, followed by Y1248H, L1213V, and D1246H (Jeffers et al., 1997; Figure 1 and Table 1). Next, analysis of focus formation, cell motility, and tumour growth in athymic mice demonstrated a correlation between MET enzymatic activity and the transforming properties of the different mutants (Bardelli et al., 1997a; Schmidt et al., 1997; Bardelli et al., 1998; Graveel et al., 2004). For instance M1268T, the most active mutant, elicited the most marked focus formation (Bardelli et al., 1998). The involvement of HGF stimulation was also investigated. The two most strongly activating variants, M1268T and Y1248H, displayed constitutive activity, being found to transform fibroblasts even in the absence of HGF (Michieli et al., 1999). In contrast, other evaluated mutations (M1149T, V1206L, L1213V, V1238I), displaying weaker activity, still required HGF stimulation for enhanced MET receptor phosphorylation and cell transformation (Chiara et al., 2003; Michieli et al., 1999). These data suggest that transformation mediated by MET mutants can depend or not on HGF, according to the initial level of kinase activation. Interestingly, mutations inducing higher MET phosphorylation (M1268T and Y1248H) occur in the C-terminal lobe of the MET receptor, specifically in or above the activation loop (Jeffers et al., 1997), while the mutations inducing lower phosphorylation (V1206L and M1149T for instance) are located in the N-lobe or near the catalytic site of the kinase domain (between the N and C lobes). This suggests a relation between mutation location and the activation level.

With knock-in mouse models for several germline MET mutations, it has been demonstrated that these MET mutations can induce spontaneous tumorigenesis. This provides strong evidence that activating MET mutations play a key role in promoting tumorigenesis (Graveel et al., 2004; Graveel et al., 2005).

For most MET mutations found in renal cancers, downstream signalling pathway activation has been little or never investigated. For two kinase mutations in the C-terminal lobe, M1268T and Y1248H, an increase in endocytosis/recycling of the receptor to the membrane has been described, along with a decrease in its degradation (Joffre et al., 2011).

While in renal cancers MET mutations are located exclusively in the kinase domain, in lung cancers they mainly affect the juxtamembrane domain, encoded by exon 14. The first juxtamembrane-domain-located mutations to be discovered were point mutations inducing amino acid substitutions within the domain (Seiwert et al., 2009; Lee et al., 2000). These mutations include R988C, P1009S, and T1010I with, for instance, about 1% of NSCLC patients harbouring R988C (Krishnaswamy et al., 2009). Several studies have demonstrated that these amino acid substitutions within the juxtamembrane domain promote migration and colony formation in soft agar and increase levels of reactive oxygen species, a phenomenon liable to participate in cell transformation (Ma, 2015; Jagadeeswaran et al., 2007). Furthermore, it has been shown that they favour the growth of experimental tumours. Whether these mutations are really activating mutations, however, is controversial, since they do not cause MET kinase activation (Lee et al., 2000; Tyner et al., 2010), so their mode of action is not obvious. In addition, recent studies have shown that these mutations can be germline mutations and thus might correspond to polymorphisms ( Tyner et al., 2010; Boland et al., 2013). Nevertheless, strong functional evidence suggests that these mutations, even present in the germline, could favour lung cancer. In the murine strain SWRJ, the presence of the R968C MET variant, corresponding to the human R988C variant, favours the development of lung tumours upon exposure to a carcinogen (Zaffaroni et al., 2005). In addition, we have recently demonstrated that the R988C mutation favours MET proteolytic cleavages by calpain, a cytoplasmic calcium-activated protease (Montagne et al., 2017). This MET cleavage leads to the generation of an intracellular fragment of about 45 kDa (p45 MET), which in epithelial cells promotes migration and invasion induced by HGF stimulation. This suggests an original mechanism of MET activation, independent of activation of its kinase (Montagne et al., 2017). It is worth noting that, in contrast to the p40 MET fragment generated during apoptosis (see next chapter), the p45 MET fragment is unable to amplify apoptosis. This suggests that differential MET processing by proteases generates specialized fragments according to the cell conditions (Fernandes et al., 2019).

Besides mutations causing amino-acid substitutions within the juxtamembrane domain, several mutations affecting the splice junctions flanking exon 14, encoding the juxtamembrane domain, were described in 2006 in two adenocarcinoma tissues and in the NSCLC cell line H596 (Kong-Beltran et al., 2006). After that, a few additional somatic alterations affecting exon 14 were described (Onozato et al., 2009; Vieira et al., 2014), but the rate of these mutations in lung cancers was not determined. In 2014, profiling of lung adenocarcinomas by whole-exome sequencing and mRNA sequencing revealed an approximate 3% rate of somatic mutations leading to exon 14 skipping in lung cancer (Collisson et al., 2014). One year later, the great diversity of MET exon 14 alterations was proved by next-generation sequencing (NGS) across several advanced cancers, including lung, gastric, colorectal, and brain cancers (Frampton et al., 2015). Since then, more than 160 different alterations affecting MET exon 14 have been described, including point mutations, deletions, insertions, and complex mutations (indels) which all affect conserved sequences of donor or acceptor splice sites (Figure 2A; Schrock et al., 2016). At the 5’ end of the exon, most of the alterations are deletions, insertions, and indels affecting the acceptor splice site, the branch point, or the polypyrimidine tract. At the 3’ end, they are mostly point mutations affecting the donor splice site (Figure 2A). Interestingly, all these alterations potentially lead to in-phase exon 14 skipping, as demonstrated by RNA sequencing (Kong-Beltran et al., 2006; Collisson et al., 2014; Davies et al., 2019). In normal mouse liver and kidney, alternative splicing affecting exon 15 (corresponding to exon 14 in human) has been described (exon 15 in transcript ID ENSMUST00000115443). It has been proved that this rare alternative splicing event induces a 141-basepair deletion predicted to result in a 47-amino-acid in-frame deletion in the juxtamembrane region of the cytoplasmic part (Lee and Yamada, 1994). This rare alternative splicing event has not been described, to date, in normal human tissues, but mouse fibroblasts expressing the MET variant with the described deletion display transforming phenotypes and form tumours in immunodeficient mice. This suggests that deletion of exon 15 (corresponding to exon 14 in human) may promote tumorigenesis (Lee et al., 2006; Baek et al., 2004). More recently, in the exon-14-encoded juxtamembrane domain of human MET, several negative regulatory sites have been characterized. The first negative regulatory mechanism found to target the juxtamembrane region was phosphorylation of serine 1003 (Ser985 in the short MET isoform). Ser1003 is phosphorylated by protein kinase C (PKC) and dephosphorylated by protein phosphatase 2 A (PP2A) (Hashigasako et al., 2004). Phosphorylation of MET Ser1003 impairs proper phosphorylation of tyrosine residues, and can thus control cell responsiveness to HGF (Gandino et al., 1994). After liver injury, it has been proved that ligand-dependent activation of the MET kinase, required for tissue regeneration, correlates with decreased Ser1003 phosphorylation (Nakayama et al., 2013). This suggests an involvement of Ser1003 in regulating MET activity in physiological processes. On this basis it would seem that deletion of exon 14 could confer insensitivity to MET-inhibiting signals conveyed by PKC, thus leading to MET activation.

Figure 2

Download asset Open asset

The second identified juxtamembrane-domain residue crucial to MET downregulation is tyrosine 1021 (Tyr1003 in the short MET isoform). Following MET activation, the phosphorylated Tyr1021 residue participates in MET ubiquitination by recruiting the E3 ubiquitin ligase CBL (Casitas B-lineage lymphoma) to the DYpR motif, through interaction with the tyrosine kinase binding domain (TKB) (Peschard et al., 2001; Figure 2B). Interestingly, the Tyr1021 mutation does not impair clathrin-dependent MET internalisation although, if the mutant is internalized, the absence of ubiquitination could prevent its efficient degradation (Li et al., 2007). It has been demonstrated that MET mutated at Tyr1021 promotes more marked cell motility and displays higher stability and a greater transforming capacity than the wild-type version (Weidner et al., 1995; Lai et al., 2012; Abella et al., 2005).

The third regulatory site on exon 14 is a caspase site involved in MET processing during apoptosis. Upon stress induction and in the absence of ligand, the MET receptor is first cleaved at a consensus caspase site in its C-terminal tail. This initial cleavage is followed by a second one, at aspartic acid 1020 (Asp1020) within an ESVD motif of the juxtamembrane domain. This leads to the generation of a 40 kDa cytoplasmic C-terminal fragment (p40 MET) containing the tyrosine kinase domain (Figure 2B; Foveau et al., 2007; Tulasne et al., 2004). During apoptosis, the level of full-length MET receptor decreases drastically after the caspase cleavages. Furthermore, the separation of the extracellular ligand-binding domain from the kinase domain prevents receptor activation by its ligand. Beside the fact that caspase cleavages inactivate the receptor, they also convert it to a pro-apoptotic fragment (p40 MET) capable of stimulating cell death, by promoting calcium flux involved in mitochondrial permeabilization (Lefebvre et al., 2013). Furthermore, in knock-in mice expressing a MET variant mutated at the C-terminal caspase cleavage site, we have highlighted that production of a functional p40 MET is important for FAS-driven hepatocyte apoptosis. Thus, MET acts in vivo as a dependence receptor, through an original signalling mechanism controlling mitochondrial permeabilization (Duplaquet et al., 2020). Caspase cleavages complement the different negative regulatory mechanisms that target this domain and are lost through exon 14 skipping. Interestingly, the ESVD1020 caspase cleavage site overlaps with the DYp1021R recruitment motif for CBL (ESVD1020Yp1021R), and phosphorylation of Y1021 prevents caspase cleavage. This suggests a mechanism protecting phosphorylated MET against caspase cleavage (Deheuninck et al., 2009).

To study the effects of MET exon 14 skipping, investigators have used a clustered regularly interspaced short palindromic repeat (CRISPR/Cas9) system to generate the METex14Del variant in several isogenic cell models (HEK293, H292, and 16HBE cells). A tumour cell line displaying MET exon 14 skipping has also been employed. It appears, firstly, that activation of the METex14Del variant still depends on ligand stimulation. Second, METex14Del induces stronger and more sustained activation of receptor kinase activity and downstream signalling pathways, including the RAS signalling pathway, resulting in significant activation of cell responses such as migration, scattering, and invasion in vitro and metastasis in vivo (Kong-Beltran et al., 2006; Fernandes et al., 2023a; Togashi et al., 2015; Frampton et al., 2015; Lu et al., 2022). Transcriptomic analyses after HGF stimulation have notably revealed expression of matrix metalloproteases known to promote motility and invasion (Cabral-Pacheco et al., 2020) and to be regulated by the RAS signalling pathway (Yang et al., 2014; Tanimura et al., 2003; Genersch et al., 2000). This suggests that sustained activation of RAS-ERK signalling by the METex14Del variant induces expression of MMPs promoting cell motility and invasion.

Only a few functional studies have explored the respective roles of the three known regulatory sites of the juxtamembrane domain in regulating receptor and downstream signalling pathway activation. It seems, however, that the CBL binding site, involved in MET ubiquitination, is a crucial regulatory site (Fernandes et al., 2023b; Miao and Xu, 2019). Furthermore, when METex14Del is present, other known oncogenic drivers such as KRAS (Kirsten rat sarcoma viral oncogene homolog), EGFR (epidermal growth factor receptor), and HER2 (human epidermal growth factor receptor 2) tend to be absent, which suggests that METex14Del can promote oncogenesis in the absence of other oncogenic drivers (Pilotto et al., 2017). The prognostic impact of MET exon 14 skipping has not yet been studied extensively, but previously untreated patients displaying MET dysregulation in NSCLC (due to MET exon 14 skipping, MET amplification, or both) display bad prognosis (Awad, 2016). These results constitute evidence that MET exon 14 skipping alterations are associated, in patients with NSCLC, with poorer outcome. This, combined with their oncogenic driver potential and their prevalence in NSCLC, makes the METex14Del variant an attractive therapeutic target.

Until very recently, the functional consequences of MET mutations affecting the extracellular domain were unknown. Some such mutations were viewed as polymorphisms without any functional consequences. Yet MET N375S, the most common polymorphism known to affect the MET gene and which causes an amino acid substitution in the semaphorin domain, is found also in several cancers, including lung cancers (Tengs et al., 2006). Interestingly, this mutation can confer exquisite binding affinity for HER2, enabling METN375S to interact with HER2 in a ligand-independent fashion. The resulting METN375S/HER2 dimer transduces potent proliferative, pro-invasive, and pro-metastatic cues through the HER2 signaling axis to drive aggressive HNSCC and LUSC cancers (Kong et al., 2020).

Strategies for inhibiting MET have been developed by pharmaceutical companies and academic laboratories. One approach is to target the HGF-MET interaction with blocking antibodies. Another is to inhibit MET kinase activity with TKIs. In 2013, Choueiri et al tested, in a phase II clinical trial, the compound foretinib, an oral multikinase TKI targeting MET, VEGF, RON, AXL, and TIE-2 receptors in PRCC patients with a MET mutation. Of the patients with a germline MET mutation, five out of ten showed a positive response, while the others showed stable disease. Of the positively responding patients, four showed a 10% reduction of the tumour. Patients without a germline MET mutation showed no such response. Foretinib thus gives rise to a high response rate in patients with a germline MET mutation, with manageable toxicity similar to that of other anti-VEGFR molecules (Choueiri et al., 2013).

In the SAVOIR phase III clinical trial, conducted on 60 patients with chromosomal 7 gain, MET amplification, MET kinase mutation, or HGF alteration, the effect of the MET TKI savolitinib was studied versus sunitinib. Although the study was prematurely terminated, it should be noted that savolitinib showed a response rate numerically superior to that of sunitinib: 27% vs 7%, respectively (Choueiri et al., 2020). Schöffski et al., conducted a phase II clinical trial (CREATE) on type I PRCC patients with MET mutations and MET amplification to test crizotinib. Progression-free survival of more than one year was demonstrated, with durable disease control in 75% of the MET-positive patients (Schöffski et al., 2017).

Finally, combination therapies have also been tested in PRCC. Combining durvalumab, a PD-L1 inhibitor, with the MET inhibitor savolitinib was studied in metastatic RCC patients. For patients with MET impairment, median progression-free survival was 12 months and overall survival was 27.4 months. Combining savolitinib and durvalumab thus seems a possibility for MET-positive tumours (Suárez et al., 2023).

Several other selective and non-selective MET inhibitors are under clinical evaluation, such as INC280 in Phase II for papillary renal cell cancer, crizotinib, and cabozantinib for papillary renal cell carcinoma type 1, and nivolumab, ipilimumab, and tivantinib for papillary renal cell carcinoma type 2 (https://www.clinicaltrials.gov/).

After initial preclinical studies demonstrating MET TKI efficacy in cell lines displaying MET exon 14 skipping mutations (Togashi et al., 2015; Frampton et al., 2015; Engstrom et al., 2017; Cecchi et al., 2016; Bladt et al., 2013), several clinical trials were performed to evaluate the efficacy of MET TKIs in NSCLC patients displaying MET exon 14 skipping. First clinical evidence of MET exon 14 skipping tumours responding to a MET TKI was obtained in studies using crizotinib, an ATP-binding competitor of anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS1), RON, and MET (Paik et al., 2015; Giroux-Leprieur et al., 2016). This TKI first showed efficacy in several case studies on patients harbouring MET exon 14 skipping tumours (Paik et al., 2015; Drilon et al., 2016; Waqar et al., 2015). Furthermore, data from a clinical trial on a relatively large cohort, in terms of the rate of MET exon 14 mutations (n=69), showed encouraging outcomes in patients with advanced NSCLC and MET exon 14 skipping, with a 9.1 month median duration of response and a 7.3 month median progression free-survival (Drilon et al., 2020). On the basis of these results, in May 2018 crizotinib received breakthrough therapy designation from the United States Food and Drug Administration (US FDA), for the treatment of metastatic NSCLC in patients with MET exon 14 skipping alterations and progression on or after platinum-based chemotherapy (Drilon et al., 2016; Pfizer, 2020). Objective responses to other MET TKIs have likewise been observed, notably in the phase II trial VISION, in which tepotinib was found to induce an objective response in half of the MET exon 14 skipping patients, with an 11 month median duration of response and a 17.1 month median duration of overall survival (Paik et al., 2020). Another MET TKI, capmatinib, gave rise to objective responses in NSCLC patients displaying a MET exon 14 mutation, including previously untreated ones (GEOMETRY trial), with a 12.6 month median response duration. These encouraging results led the Japanese Ministry of Health to approve treatment with TEPMETKO* (tepotinib) for NSCLC patients with MET exon 14 mutations (Merck Global, 2020). At the same time, the US FDA granted approval of capmatinib for treating NSCLC patients harbouring MET exon14 mutations (Novartis, 2020). Combined, the preclinical and clinical evidence proves that patients with MET exon 14 skipping alterations are treatable with MET TKIs, some of which are still under clinical development (Hu et al., 2018; Landi et al., 2019; Yan et al., 2018).

Over the last few years and as a consequence of the efficacy of MET TKIs in patients harbouring MET exon 14 skipping mutations, several MET TKIs (crizotinib, glesatinib, capmatinib, tepotinib) have been used in the context of clinical trials or as off-label treatments . Yet as expected for targeted therapies, after initial responses, resistances have systematically been observed. Many resistance mechanisms have been described, mostly involving activation of the usual suspects, such as other RTKs or downstream signaling hubs (Jamme et al., 2020; Suzawa et al., 2019). Some resistances, however, are due to on-target mutations, essentially in the MET kinase domain. In the context of this review, we can thus state that MET resists its own targeting.

The following mutated amino acids have been clinically described after treatment with a MET TKI in patients harbouring MET exon 14 skipping mutations: H1112, G1181, L1213, F1218, D1246, and Y1248, which usually emerge after only a few months of treatment with crizotinib, glesatinib, or capmatinib (Figure 3A and B; Awad et al., 2018; Dong et al., 2016; Guo et al., 2019; Heist et al., 2016; Jin et al., 2019; Li et al., 2017; Ou et al., 2017; Recondo et al., 2020; Rotow et al., 2018; Zhang et al., 2017). The presence of multiple mutations in the kinase domain has also been observed (Awad et al., 2018; Li et al., 2017; Recondo et al., 2020; Rotow et al., 2018; Dong et al., 2016). For example, D1246N/H has been found with Y1248H (Dong et al., 2016) and G1181R can be present with L1213V, D1246H/N, and Y1248H/S (Recondo et al., 2020) in a patient’s circulating DNA.

Figure 3 with 2 supplements see all

Download asset Open asset

In the recent study of Recondo et al., among 20 patients with MET exon 14-skipping mutations who showed resistance to a MET TKI, seven (35%) displayed on-target resistances due to MET mutations, the other resistances being off-target ones (Recondo et al., 2020).

Most of the MET mutations recently found associated with resistance to TKIs were already known as MET-activating mutations, notably in renal cancer (Jeffers et al., 1997; Jeffers and Vande Woude, 1999; Maritano et al., 2000). Detection of these mutations in tumours suggests that they may play a direct role in resistance through ligand-independent MET activation.

Resistance to MET TKIs has also been investigated in cell models displaying MET exon 14 skipping and/or MET exon 14 skipping oncogene dependence. In Ba/F3 cells engineered to depend, for their growth, on ectopic expression of an oncogene rather than on a cytokine, 12 MET resistance mutations were revealed, including five at residues previously spotted in patients (G1181, L1213, F1218, D1246, and T1248) (Fujino et al., 2019). Interestingly, mutations at positions 1246 and 1248 were involved in resistance to type I TKIs, which bind the active form of MET, while mutations at 1213 and 1218 were involved in resistance to type II TKIs, which bind the inactive form. This study thus suggests that the contribution of specific mutations to resistance may depend on the type of TKI (Fujino et al., 2019). These data are also in agreement with the view that a conformational change induced by a particular mutation in the kinase domain may interfere with the binding of particular MET TKIs. For instance, the resistance mutations at positions 1181 and 1248 are consistent with steric hindrance of crizotinib binding (crizotinib being a type I TKI) (Figure 3B; Figure 3—video 1), while the resistance mutations at positions 1213 and 1218 are consistent with steric hindrance merestinib binding, the latter being a type II TKI (Figure 3B; Figure 3—video 2). Interestingly, MET variants with resistance mutations against type I TKIs appear to be sensitive to type II inhibitors, and vice versa (Fujino et al., 2019). This suggests that resistance might be overcome through the complementary activity of different MET TKIs. Similar results have been obtained on NIH3T3 cells: expression of a MET variant displaying both exon 14 skipping and a D1246N or Y1248C mutation was found to drive resistance to type I but not type II inhibitors (Engstrom et al., 2017). In the same publication, the authors report a patient with a MET exon 14 skipping mutation who displayed resistance to crizotinib, associated with the presence of the following additional MET mutations: D1246N, Y1248H/S, and G1181R. On the basis of results obtained on cell models, treatment was switched from the type I inhibitor crizotinib to the type II inhibitor glesatinib. This led to the regression of some metastatic localizations, with disappearance of the Y1248H/S mutation. This disappearance was concomitant, however, with the appearance of an L1213V mutation (Engstrom et al., 2017), identified in a study by Fujino et al., 2019 as leading to resistance to type II TKIs.

On-target resistance has also been described in the context of MET gene amplification. A case report describes a patient with an initial EGFR-activating mutation, who developed primary resistance to an EGFR TKI through MET amplification (Bahcall et al., 2016). Co-treatment with an EGFR TKI and the MET TKI savolitinib led to a dramatic positive clinical response, but after several months of co-treatment, the patient experienced a relapse associated with detection of an additional MET D1246V mutation, previously described as an activating mutation (Jeffers et al., 1997). In the same study, interestingly, the authors demonstrated with reconstituted MET mutations in cell lines that the D1246V mutant is resistant to type I TKIs (including savolitinib), but not to type II MET inhibitors. This finding led to adapting the treatment: the EGFR TKI was used with cabozantinib, a type II MET TKI. To this treatment, the progressive lung disease responded very well (Bahcall et al., 2016). In a recent study on patients displaying MET gene amplification (following or not treatment with EGFR TKI), treatments with various TKIs led to the appearance of potential resistance mutations, including substitutions at D1246 and Y1248. Interestingly, similar mutations have been found in the context of exon 14 skipping (Yao et al., 2023), suggesting that at least the main on-target resistances are common between the WT MET receptor and the METex14Del variant.

1. 1. Abella JV
   2. Peschard P
   3. Naujokas MA
   4. Lin T
   5. Saucier C
   6. Urbé S
   7. Park M

   (2005) Met/Hepatocyte growth factor receptor ubiquitination suppresses transformation and is required for Hrs phosphorylation

   Molecular and Cellular Biology 25:9632–9645.

   https://doi.org/10.1128/MCB.25.21.9632-9645.2005

   • PubMed
   • Google Scholar
2. 1. Akhtar M
   2. Al-Bozom IA
   3. Al Hussain T

   (2019) Papillary renal cell carcinoma (prcc): an update

   Advances in Anatomic Pathology 26:124–132.

   https://doi.org/10.1097/PAP.0000000000000220

   • PubMed
   • Google Scholar
3. 1. Asaoka Y
   2. Tada M
   3. Ikenoue T
   4. Seto M
   5. Imai M
   6. Miyabayashi K
   7. Yamamoto K
   8. Yamamoto S
   9. Kudo Y
   10. Mohri D
   11. Isomura Y
   12. Ijichi H
   13. Tateishi K
   14. Kanai F
   15. Ogawa S
   16. Omata M
   17. Koike K

   (2010) Gastric cancer cell line hs746t harbors a splice site mutation of c-met causing juxtamembrane domain deletion

   Biochemical and Biophysical Research Communications 394:1042–1046.

   https://doi.org/10.1016/j.bbrc.2010.03.120

   • PubMed
   • Google Scholar
4. 1. Awad MM

   (2016) Impaired c-met receptor degradation mediated by met exon 14 mutations in non-small-cell lung cancer

   Journal of Clinical Oncology 34:879–881.

   https://doi.org/10.1200/JCO.2015.64.2777

   • PubMed
   • Google Scholar
5. 1. Awad MM
   2. Bahcall M
   3. Sholl LM
   4. Wilson FH
   5. Paweletz C
   6. Capelletti M
   7. Leonardi GC
   8. Watanabe M
   9. Baba H
   10. Chambers ES
   11. Redig AJ
   12. Nishino M
   13. VanderLaan PA
   14. Costa DB
   15. Imamura Y
   16. Janne PA

   (2018) Mechanisms of acquired resistance to met tyrosine kinase inhibitors (tkis) in met exon 14 (metex14) mutant non-small cell lung cancer (nsclc)

   Journal of Clinical Oncology 36:9069.

   https://doi.org/10.1200/JCO.2018.36.15_suppl.9069

   • Google Scholar
6. 1. Baek CM
   2. Jeon SH
   3. Jang JJ
   4. Lee BS
   5. Lee JH

   (2004) Transforming variant of Met receptor confers serum independence and anti-apoptotic property and could be involved in the mouse thymic lymphomagenesis

   Experimental & Molecular Medicine 36:283–291.

   https://doi.org/10.1038/emm.2004.39

   • PubMed
   • Google Scholar
7. 1. Bahcall M
   2. Sim T
   3. Paweletz CP
   4. Patel JD
   5. Alden RS
   6. Kuang Y
   7. Sacher AG
   8. Kim ND
   9. Lydon CA
   10. Awad MM
   11. Jaklitsch MT
   12. Sholl LM
   13. Jänne PA
   14. Oxnard GR

   (2016) Acquired metd1228v mutation and resistance to met inhibition in lung cancer

   Cancer Discovery 6:1334–1341.

   https://doi.org/10.1158/2159-8290.CD-16-0686

   • PubMed
   • Google Scholar
8. 1. Bardelli A
   2. Longati P
   3. Gramaglia D
   4. Stella MC
   5. Comoglio PM

   (1997a) Gab1 coupling to the HGF/Met receptor multifunctional docking site requires binding of Grb2 and correlates with the transforming potential

   Oncogene 15:3103–3111.

   https://doi.org/10.1038/sj.onc.1201561

   • PubMed
   • Google Scholar
9. 1. Bardelli A
   2. Pugliese L
   3. Comoglio PM

   (1997b) “Invasive-growth” signaling by the Met/HGF receptor: the hereditary renal carcinoma connection

   Biochimica et Biophysica Acta 1333:M41–M51.

   https://doi.org/10.1016/s0304-419x(97)00026-7

   • PubMed
   • Google Scholar
10. 1. Bardelli A
    2. Longati P
    3. Gramaglia D
    4. Basilico C
    5. Tamagnone L
    6. Giordano S
    7. Ballinari D
    8. Michieli P
    9. Comoglio PM

    (1998) Uncoupling signal transducers from oncogenic MET mutants abrogates cell transformation and inhibits invasive growth

    PNAS 95:14379–14383.

    https://doi.org/10.1073/pnas.95.24.14379

    • PubMed
    • Google Scholar
11. 1. Bladt F
    2. Riethmacher D
    3. Isenmann S
    4. Aguzzi A
    5. Birchmeier C

    (1995) Essential role for the c-met receptor in the migration of myogenic precursor cells into the limb bud

    Nature 376:768–771.

    https://doi.org/10.1038/376768a0

    • PubMed
    • Google Scholar
12. 1. Bladt F
    2. Faden B
    3. Friese-Hamim M
    4. Knuehl C
    5. Wilm C
    6. Fittschen C
    7. Grädler U
    8. Meyring M
    9. Dorsch D
    10. Jaehrling F
    11. Pehl U
    12. Stieber F
    13. Schadt O
    14. Blaukat A

    (2013) EMD 1214063 and EMD 1204831 constitute a new class of potent and highly selective c-Met inhibitors

    Clinical Cancer Research 19:2941–2951.

    https://doi.org/10.1158/1078-0432.CCR-12-3247

    • PubMed
    • Google Scholar
13. 1. Boland JM
    2. Jang JS
    3. Li J
    4. Lee AM
    5. Wampfler JA
    6. Erickson-Johnson MR
    7. Soares I
    8. Yang P
    9. Jen J
    10. Oliveira AM
    11. Yi ES

    (2013) MET and EGFR mutations identified in ALK-rearranged pulmonary adenocarcinoma: molecular analysis of 25 ALK-positive cases

    Journal of Thoracic Oncology 8:574–581.

    https://doi.org/10.1097/JTO.0b013e318287c395

    • PubMed
    • Google Scholar
14. 1. Cabral-Pacheco GA
    2. Garza-Veloz I
    3. Castruita-De la Rosa C
    4. Ramirez-Acuña JM
    5. Perez-Romero BA
    6. Guerrero-Rodriguez JF
    7. Martinez-Avila N
    8. Martinez-Fierro ML

    (2020) The roles of matrix metalloproteinases and their inhibitors in human diseases

    International Journal of Molecular Sciences 21:9739.

    https://doi.org/10.3390/ijms21249739

    • PubMed
    • Google Scholar
15. Website

    1. Cancer Genome Atlas Research Network

    (2023) Comprehensive genomic characterization defines human glioblastoma genes and core494 pathways - PubMed

    Accessed April 24, 2023.

    https://pubmed.ncbi.nlm.nih.gov/18772890/
16. 1. Cecchi F
    2. Rabizadeh S
    3. Weingarten P
    4. Tsai C
    5. Zhou L
    6. Hembrough T

    (2016) P-038 MET activation via exon 14 skipping mutations (METex14del): gastrointestinal prevalence and sensitivity to MET inhibitor AMG337

    Annals of Oncology 27:ii11.

    https://doi.org/10.1093/annonc/mdw199.36

    • Google Scholar
17. 1. Chiara F
    2. Michieli P
    3. Pugliese L
    4. Comoglio PM

    (2003) Mutations in the met oncogene unveil a “dual switch” mechanism controlling tyrosine kinase activity

    The Journal of Biological Chemistry 278:29352–29358.

    https://doi.org/10.1074/jbc.M302404200

    • PubMed
    • Google Scholar
18. 1. Choueiri TK
    2. Vaishampayan U
    3. Rosenberg JE
    4. Logan TF
    5. Harzstark AL
    6. Bukowski RM
    7. Rini BI
    8. Srinivas S
    9. Stein MN
    10. Adams LM
    11. Ottesen LH
    12. Laubscher KH
    13. Sherman L
    14. McDermott DF
    15. Haas NB
    16. Flaherty KT
    17. Ross R
    18. Eisenberg P
    19. Meltzer PS
    20. Merino MJ
    21. Bottaro DP
    22. Linehan WM
    23. Srinivasan R

    (2013) Phase II and biomarker study of the dual MET/VEGFR2 inhibitor foretinib in patients with papillary renal cell carcinoma

    Journal of Clinical Oncology 31:181–186.

    https://doi.org/10.1200/JCO.2012.43.3383

    • PubMed
    • Google Scholar
19. 1. Choueiri TK
    2. Heng DYC
    3. Lee JL
    4. Cancel M
    5. Verheijen RB
    6. Mellemgaard A
    7. Ottesen LH
    8. Frigault MM
    9. L’Hernault A
    10. Szijgyarto Z
    11. Signoretti S
    12. Albiges L

    (2020) Efficacy of savolitinib vs sunitinib in patients with met-driven papillary renal cell carcinoma: the savoir phase 3 randomized clinical trial

    JAMA Oncology 6:1247–1255.

    https://doi.org/10.1001/jamaoncol.2020.2218

    • PubMed
    • Google Scholar
20. 1. Collisson EA
    2. Campbell JD
    3. Brooks AN
    4. Berger AH
    5. Lee W
    6. Chmielecki J

    (2014) Comprehensive molecular profiling of lung adenocarcinoma

    Nature 511:543–550.

    https://doi.org/10.1038/nature13385

    • PubMed
    • Google Scholar
21. 1. Cortot AB
    2. Kherrouche Z
    3. Descarpentries C
    4. Wislez M
    5. Baldacci S
    6. Furlan A
    7. Tulasne D

    (2017) Exon 14 deleted met receptor as a new biomarker and target in cancers

    Journal of the National Cancer Institute 109:109.

    https://doi.org/10.1093/jnci/djw262

    • PubMed
    • Google Scholar
22. 1. Davies KD
    2. Lomboy A
    3. Lawrence CA
    4. Yourshaw M
    5. Bocsi GT
    6. Camidge DR
    7. Aisner DL

    (2019) Dna-based versus rna-based detection of met exon 14 skipping events in lung cancer

    Journal of Thoracic Oncology 14:737–741.

    https://doi.org/10.1016/j.jtho.2018.12.020

    • PubMed
    • Google Scholar
23. 1. Deheuninck J
    2. Goormachtigh G
    3. Foveau B
    4. Ji Z
    5. Leroy C
    6. Ancot F
    7. Villeret V
    8. Tulasne D
    9. Fafeur V

    (2009) Phosphorylation of the MET receptor on juxtamembrane tyrosine residue 1001 inhibits its caspase-dependent cleavage

    Cellular Signalling 21:1455–1463.

    https://doi.org/10.1016/j.cellsig.2009.05.005

    • PubMed
    • Google Scholar
24. 1. Dong HJ
    2. Li P
    3. Wu CL
    4. Zhou XY
    5. Lu HJ
    6. Zhou T

    (2016) Response and acquired resistance to crizotinib in chinese patients with lung adenocarcinomas harboring MET Exon 14 splicing alternations

    Lung Cancer 102:118–121.

    https://doi.org/10.1016/j.lungcan.2016.11.006

    • PubMed
    • Google Scholar
25. 1. Drilon AE
    2. Camidge DR
    3. Ou SHI
    4. Clark JW
    5. Socinski MA
    6. Weiss J
    7. Riely GJ
    8. Winter M
    9. Wang SC
    10. Monti K
    11. Wilner KD
    12. Paik PK

    (2016) Efficacy and safety of crizotinib in patients (pts) with advanced MET exon 14-altered non-small cell lung cancer (NSCLC)

    Journal of Clinical Oncology 34:108.

    https://doi.org/10.1200/JCO.2016.34.15_suppl.108

    • Google Scholar
26. 1. Drilon A
    2. Clark JW
    3. Weiss J
    4. Ou SHI
    5. Camidge DR
    6. Solomon BJ
    7. Otterson GA
    8. Villaruz LC
    9. Riely GJ
    10. Heist RS
    11. Awad MM
    12. Shapiro GI
    13. Satouchi M
    14. Hida T
    15. Hayashi H
    16. Murphy DA
    17. Wang SC
    18. Li S
    19. Usari T
    20. Wilner KD
    21. Paik PK

    (2020) Antitumor activity of crizotinib in lung cancers harboring a MET exon 14 alteration

    Nature Medicine 26:47–51.

    https://doi.org/10.1038/s41591-019-0716-8

    • PubMed
    • Google Scholar
27. 1. Duplaquet L
    2. Kherrouche Z
    3. Baldacci S
    4. Jamme P
    5. Cortot AB
    6. Copin MC
    7. Tulasne D

    (2018) The multiple paths towards MET receptor addiction in cancer

    Oncogene 37:3200–3215.

    https://doi.org/10.1038/s41388-018-0185-4

    • PubMed
    • Google Scholar
28. 1. Duplaquet L
    2. Leroy C
    3. Vinchent A
    4. Paget S
    5. Lefebvre J
    6. Vanden Abeele F
    7. Lancel S
    8. Giffard F
    9. Paumelle R
    10. Bidaux G
    11. Heliot L
    12. Poulain L
    13. Furlan A
    14. Tulasne D

    (2020) Control of cell death/survival balance by the MET dependence receptor

    eLife 9:e50041.

    https://doi.org/10.7554/eLife.50041

    • PubMed
    • Google Scholar
29. 1. Engstrom LD
    2. Aranda R
    3. Lee M
    4. Tovar EA
    5. Essenburg CJ
    6. Madaj Z
    7. Chiang H
    8. Briere D
    9. Hallin J
    10. Lopez-Casas PP
    11. Baños N
    12. Menendez C
    13. Hidalgo M
    14. Tassell V
    15. Chao R
    16. Chudova DI
    17. Lanman RB
    18. Olson P
    19. Bazhenova L
    20. Patel SP
    21. Graveel C
    22. Nishino M
    23. Shapiro GI
    24. Peled N
    25. Awad MM
    26. Jänne PA
    27. Christensen JG

    (2017) Glesatinib exhibits antitumor activity in lung cancer models and patients harboring MET exon 14 mutations and overcomes mutation-mediated resistance to type I MET inhibitors in nonclinical models

    Clinical Cancer Research 23:6661–6672.

    https://doi.org/10.1158/1078-0432.CCR-17-1192

    • PubMed
    • Google Scholar
30. 1. Fernandes M
    2. Duplaquet L
    3. Tulasne D

    (2019) Proteolytic cleavages of MET: the divide-and-conquer strategy of a receptor tyrosine kinase

    BMB Reports 52:239–249.

    https://doi.org/10.5483/BMBRep.2019.52.4.024

    • PubMed
    • Google Scholar
31. 1. Fernandes M
    2. Hoggard B
    3. Jamme P
    4. Paget S
    5. Truong M-J
    6. Grégoire V
    7. Vinchent A
    8. Descarpentries C
    9. Morabito A
    10. Stanislovas J
    11. Farage E
    12. Meneboo J-P
    13. Sebda S
    14. Bouchekioua-Bouzaghou K
    15. Nollet M
    16. Humez S
    17. Perera T
    18. Fromme P
    19. Grumolato L
    20. Figeac M
    21. Copin M-C
    22. Tulasne D
    23. Cortot AB
    24. Kermorgant S
    25. Kherrouche Z

    (2023a) MET exon 14 skipping mutation is a hepatocyte growth factor (HGF)-dependent oncogenic driver in vitro and in humanised HGF knock-in mice

    Molecular Oncology 17:2257–2274.

    https://doi.org/10.1002/1878-0261.13397

    • PubMed
    • Google Scholar
32. 1. Fernandes M
    2. Paget S
    3. Kherrouche Z
    4. Truong M-J
    5. Vinchent A
    6. Meneboo J-P
    7. Sebda S
    8. Werkmeister E
    9. Descarpentries C
    10. Figeac M
    11. Cortot AB
    12. Tulasne D

    (2023b) Transforming properties of MET receptor exon 14 skipping can be recapitulated by loss of the CBL ubiquitin ligase binding site

    FEBS Letters 597:2301–2315.

    https://doi.org/10.1002/1873-3468.14702

    • PubMed
    • Google Scholar
33. 1. Foveau B
    2. Leroy C
    3. Ancot F
    4. Deheuninck J
    5. Ji Z
    6. Fafeur V
    7. Tulasne D

    (2007) Amplification of apoptosis through sequential caspase cleavage of the MET tyrosine kinase receptor

    Cell Death and Differentiation 14:752–764.

    https://doi.org/10.1038/sj.cdd.4402080

    • PubMed
    • Google Scholar
34. 1. Frampton GM
    2. Ali SM
    3. Rosenzweig M
    4. Chmielecki J
    5. Lu X
    6. Bauer TM
    7. Akimov M
    8. Bufill JA
    9. Lee C
    10. Jentz D
    11. Hoover R
    12. Ou S-HI
    13. Salgia R
    14. Brennan T
    15. Chalmers ZR
    16. Jaeger S
    17. Huang A
    18. Elvin JA
    19. Erlich R
    20. Fichtenholtz A
    21. Gowen KA
    22. Greenbowe J
    23. Johnson A
    24. Khaira D
    25. McMahon C
    26. Sanford EM
    27. Roels S
    28. White J
    29. Greshock J
    30. Schlegel R
    31. Lipson D
    32. Yelensky R
    33. Morosini D
    34. Ross JS
    35. Collisson E
    36. Peters M
    37. Stephens PJ
    38. Miller VA

    (2015) Activation of met via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to met inhibitors

    Cancer Discovery 5:850–859.

    https://doi.org/10.1158/2159-8290.CD-15-0285

    • Google Scholar
35. 1. Fujino T
    2. Kobayashi Y
    3. Suda K
    4. Koga T
    5. Nishino M
    6. Ohara S
    7. Chiba M
    8. Shimoji M
    9. Tomizawa K
    10. Takemoto T
    11. Mitsudomi T

    (2019) Sensitivity and resistance of met exon 14 mutations in lung cancer to eight met tyrosine kinase inhibitors in vitro

    Journal of Thoracic Oncology 14:1753–1765.

    https://doi.org/10.1016/j.jtho.2019.06.023

    • PubMed
    • Google Scholar
36. 1. Gandino L
    2. Longati P
    3. Medico E
    4. Prat M
    5. Comoglio PM

    (1994)

    Phosphorylation of serine 985 negatively regulates the hepatocyte growth factor receptor kinase

    The Journal of Biological Chemistry 269:1815–1820.

    • PubMed
    • Google Scholar
37. 1. Genersch E
    2. Hayess K
    3. Neuenfeld Y
    4. Haller H

    (2000) Sustained ERK phosphorylation is necessary but not sufficient for MMP-9 regulation in endothelial cells: involvement of Ras-dependent and -independent pathways

    Journal of Cell Science 113 Pt 23:4319–4330.

    https://doi.org/10.1242/jcs.113.23.4319

    • PubMed
    • Google Scholar
38. 1. Gherardi E
    2. Youles ME
    3. Miguel RN
    4. Blundell TL
    5. Iamele L
    6. Gough J
    7. Bandyopadhyay A
    8. Hartmann G
    9. Butler PJG

    (2003) Functional map and domain structure of MET, the product of the c-MET protooncogene and receptor for hepatocyte growth factor/scatter factor

    PNAS 100:12039–12044.

    https://doi.org/10.1073/pnas.2034936100

    • PubMed
    • Google Scholar
39. 1. Gherardi E
    2. Sandin S
    3. Petoukhov MV
    4. Finch J
    5. Youles ME
    6. Ofverstedt LG
    7. Miguel RN
    8. Blundell TL
    9. Vande Woude GF
    10. Skoglund U
    11. Svergun DI

    (2006) Structural basis of hepatocyte growth factor/scatter factor and MET signalling

    PNAS 103:4046–4051.

    https://doi.org/10.1073/pnas.0509040103

    • PubMed
    • Google Scholar
40. 1. Giroux-Leprieur E
    2. Fallet V
    3. Cadranel J
    4. Wislez M

    (2016) Spotlight on crizotinib in the first-line treatment of ALK-positive advanced non-small-cell lung cancer: patients selection and perspectives

    Lung Cancer 7:83–90.

    https://doi.org/10.2147/LCTT.S99303

    • PubMed
    • Google Scholar
41. 1. Graveel C
    2. Su Y
    3. Koeman J
    4. Wang L-M
    5. Tessarollo L
    6. Fiscella M
    7. Birchmeier C
    8. Swiatek P
    9. Bronson R
    10. Vande Woude G

    (2004) Activating met mutations produce unique tumor profiles in mice with selective duplication of the mutant allele

    PNAS 101:17198–17203.

    https://doi.org/10.1073/pnas.0407651101

    • PubMed
    • Google Scholar
42. 1. Graveel CR
    2. London CA
    3. Vande Woude GF

    (2005) A mouse model of activating Met mutations

    Cell Cycle 4:518–520.

    https://doi.org/10.4161/cc.4.4.1590

    • PubMed
    • Google Scholar
43. 1. Guo R
    2. Offin M
    3. Brannon AR
    4. Chow A
    5. Delasos L
    6. Somwar R
    7. Wilkins O
    8. Scott K
    9. Tian Y
    10. Cecchi F
    11. Hembrough TA
    12. Li BT
    13. Rudin CM
    14. Kris MG
    15. Arcila ME
    16. Rekhtman N
    17. Paik PK
    18. Ladanyi M
    19. Zehir A
    20. Drilon AE

    (2019) MET inhibitor resistance in patients with MET exon 14-altered lung cancers

    Journal of Clinical Oncology 37:9006.

    https://doi.org/10.1200/JCO.2019.37.15_suppl.9006

    • Google Scholar
44. 1. Hashigasako A
    2. Machide M
    3. Nakamura T
    4. Matsumoto K
    5. Nakamura T

    (2004) Bi-directional regulation of Ser-985 phosphorylation of C-met via protein kinase C and protein phosphatase 2A involves C-Met activation and cellular responsiveness to hepatocyte growth factor

    The Journal of Biological Chemistry 279:26445–26452.

    https://doi.org/10.1074/jbc.M314254200

    • PubMed
    • Google Scholar
45. 1. Heist RS
    2. Sequist LV
    3. Borger D
    4. Gainor JF
    5. Arellano RS
    6. Le LP
    7. Dias-Santagata D
    8. Clark JW
    9. Engelman JA
    10. Shaw AT
    11. Iafrate AJ

    (2016) Acquired resistance to crizotinib in nsclc with met exon 14 skipping

    Journal of Thoracic Oncology 11:1242–1245.

    https://doi.org/10.1016/j.jtho.2016.06.013

    • PubMed
    • Google Scholar
46. 1. Hu H
    2. Mu Q
    3. Bao Z
    4. Chen Y
    5. Liu Y
    6. Chen J
    7. Wang K
    8. Wang Z
    9. Nam Y
    10. Jiang B
    11. Sa JK
    12. Cho HJ
    13. Her NG
    14. Zhang C
    15. Zhao Z
    16. Zhang Y
    17. Zeng F
    18. Wu F
    19. Kang X
    20. Liu Y
    21. Qian Z
    22. Wang Z
    23. Huang R
    24. Wang Q
    25. Zhang W
    26. Qiu X
    27. Li W
    28. Nam DH
    29. Fan X
    30. Wang J
    31. Jiang T

    (2018) Mutational landscape of secondary glioblastoma guides met-targeted trial in brain tumor

    Cell 175:1665–1678.

    https://doi.org/10.1016/j.cell.2018.09.038

    • PubMed
    • Google Scholar
47. 1. Jagadeeswaran R
    2. Ma PC
    3. Seiwert TY
    4. Jagadeeswaran S
    5. Zumba O
    6. Nallasura V
    7. Ahmed S
    8. Filiberti R
    9. Paganuzzi M
    10. Puntoni R
    11. Kratzke RA
    12. Gordon GJ
    13. Sugarbaker DJ
    14. Bueno R
    15. Janamanchi V
    16. Bindokas VP
    17. Kindler HL
    18. Salgia R

    (2006) Functional analysis of c-Met/hepatocyte growth factor pathway in malignant pleural mesothelioma

    Cancer Research 66:352–361.

    https://doi.org/10.1158/0008-5472.CAN-04-4567

    • PubMed
    • Google Scholar
48. 1. Jagadeeswaran R
    2. Jagadeeswaran S
    3. Bindokas VP
    4. Salgia R

    (2007) Activation of HGF/c-Met pathway contributes to the reactive oxygen species generation and motility of small cell lung cancer cells

    American Journal of Physiology. Lung Cellular and Molecular Physiology 292:L1488–L1494.

    https://doi.org/10.1152/ajplung.00147.2006

    • PubMed
    • Google Scholar
49. 1. Jamme P
    2. Fernandes M
    3. Copin MC
    4. Descarpentries C
    5. Escande F
    6. Morabito A
    7. Grégoire V
    8. Jamme M
    9. Baldacci S
    10. Tulasne D
    11. Kherrouche Z
    12. Cortot AB

    (2020) Alterations in the pi3k pathway drive resistance to met inhibitors in nsclc harboring met exon 14 skipping mutations

    Journal of Thoracic Oncology 15:741–751.

    https://doi.org/10.1016/j.jtho.2020.01.027

    • PubMed
    • Google Scholar
50. 1. Jardim DLF
    2. Falchook G
    3. Tang C
    4. Zinner R
    5. Wheler JJ
    6. Janku F
    7. Subbiah V
    8. Piha-Paul SA
    9. Fu S
    10. Hess K
    11. Roy-Chowdhuri S
    12. Moulder S
    13. Gonzalez-Angulo AM
    14. Meric-Bernstam F
    15. Hong DS

    (2014) Analysis of MET genetic aberrations in patients with breast cancer at MD Anderson Phase I unit

    Clinical Breast Cancer 14:468–474.

    https://doi.org/10.1016/j.clbc.2014.06.001

    • PubMed
    • Google Scholar
51. 1. Jeffers M
    2. Schmidt L
    3. Nakaigawa N
    4. Webb CP
    5. Weirich G
    6. Kishida T
    7. Zbar B
    8. Vande Woude GF

    (1997) Activating mutations for the met tyrosine kinase receptor in human cancer

    PNAS 94:11445–11450.

    https://doi.org/10.1073/pnas.94.21.11445

    • PubMed
    • Google Scholar
52. 1. Jeffers M
    2. Fiscella M
    3. Webb CP
    4. Anver M
    5. Koochekpour S
    6. Vande Woude GF

    (1998) The mutationally activated Met receptor mediates motility and metastasis

    PNAS 95:14417–14422.

    https://doi.org/10.1073/pnas.95.24.14417

    • PubMed
    • Google Scholar
53. 1. Jeffers MF
    2. Vande Woude GF

    (1999) Activating mutations in the Met receptor overcome the requirement for autophosphorylation of tyrosines crucial for wild type signaling

    Oncogene 18:5120–5125.

    https://doi.org/10.1038/sj.onc.1202902

    • PubMed
    • Google Scholar
54. 1. Jin W
    2. Shan B
    3. Liu H
    4. Zhou S
    5. Li W
    6. Pan J
    7. Lin L
    8. Hu D
    9. Pan Y

    (2019) Acquired mechanism of crizotinib resistance in nsclc with met exon 14 skipping

    Journal of Thoracic Oncology 14:e137–e139.

    https://doi.org/10.1016/j.jtho.2019.04.021

    • PubMed
    • Google Scholar
55. 1. Joffre C
    2. Barrow R
    3. Ménard L
    4. Calleja V
    5. Hart IR
    6. Kermorgant S

    (2011) A direct role for Met endocytosis in tumorigenesis

    Nature Cell Biology 13:827–837.

    https://doi.org/10.1038/ncb2257

    • PubMed
    • Google Scholar
56. 1. Kong LR
    2. Mohamed Salleh NAB
    3. Ong RW
    4. Tan TZ
    5. Syn NL
    6. Goh RM
    7. Fhu CW
    8. Tan DSW
    9. Iyer NG
    10. Kannan S
    11. Verma CS
    12. Lim YC
    13. Soo R
    14. Ho J
    15. Huang Y
    16. Lim JSJ
    17. Yan BJ
    18. Nga ME
    19. Lim SG
    20. Koeffler HP
    21. Lee SC
    22. Kappei D
    23. Hung HT
    24. Goh BC

    (2020) A common MET polymorphism harnesses HER2 signaling to drive aggressive squamous cell carcinoma

    Nature Communications 11:1556.

    https://doi.org/10.1038/s41467-020-15318-5

    • PubMed
    • Google Scholar
57. 1. Kong-Beltran M
    2. Seshagiri S
    3. Zha J
    4. Zhu W
    5. Bhawe K
    6. Mendoza N
    7. Holcomb T
    8. Pujara K
    9. Stinson J
    10. Fu L
    11. Severin C
    12. Rangell L
    13. Schwall R
    14. Amler L
    15. Wickramasinghe D
    16. Yauch R

    (2006) Somatic mutations lead to an oncogenic deletion of met in lung cancer

    Cancer Research 66:283–289.

    https://doi.org/10.1158/0008-5472.CAN-05-2749

    • PubMed
    • Google Scholar
58. 1. Krishnaswamy S
    2. Kanteti R
    3. Duke-Cohan JS
    4. Loganathan S
    5. Liu W
    6. Ma PC
    7. Sattler M
    8. Singleton PA
    9. Ramnath N
    10. Innocenti F
    11. Nicolae DL
    12. Ouyang Z
    13. Liang J
    14. Minna J
    15. Kozloff MF
    16. Ferguson MK
    17. Natarajan V
    18. Wang YC
    19. Garcia JGN
    20. Vokes EE
    21. Salgia R

    (2009) Ethnic differences and functional analysis of MET mutations in lung cancer

    Clinical Cancer Research 15:5714–5723.

    https://doi.org/10.1158/1078-0432.CCR-09-0070

    • PubMed
    • Google Scholar
59. 1. Lai AZ
    2. Durrant M
    3. Zuo D
    4. Ratcliffe CDH
    5. Park M

    (2012) Met kinase-dependent loss of the E3 ligase Cbl in gastric cancer

    The Journal of Biological Chemistry 287:8048–8059.

    https://doi.org/10.1074/jbc.M112.339820

    • PubMed
    • Google Scholar
60. 1. Landi L
    2. Chiari R
    3. Tiseo M
    4. D’Incà F
    5. Dazzi C
    6. Chella A
    7. Delmonte A
    8. Bonanno L
    9. Giannarelli D
    10. Cortinovis DL
    11. de Marinis F
    12. Borra G
    13. Morabito A
    14. Gridelli C
    15. Galetta D
    16. Barbieri F
    17. Grossi F
    18. Capelletto E
    19. Minuti G
    20. Mazzoni F
    21. Verusio C
    22. Bria E
    23. Alì G
    24. Bruno R
    25. Proietti A
    26. Fontanini G
    27. Crinò L
    28. Cappuzzo F

    (2019) Crizotinib in MET-deregulated or ROS1-rearranged pretreated non-small cell lung cancer (METROS): a phase II, prospective, multicenter, two-arms trial

    Clinical Cancer Research 25:7312–7319.

    https://doi.org/10.1158/1078-0432.CCR-19-0994

    • PubMed
    • Google Scholar
61. 1. Lee CC
    2. Yamada KM

    (1994)

    Identification of a novel type of alternative splicing of a tyrosine kinase receptor: juxtamembrane deletion of the C-met protein kinase C serine phosphorylation regulatory site

    The Journal of Biological Chemistry 269:19457–19461.

    • PubMed
    • Google Scholar
62. 1. Lee JH
    2. Han SU
    3. Cho H
    4. Jennings B
    5. Gerrard B
    6. Dean M
    7. Schmidt L
    8. Zbar B
    9. Vande Woude GF

    (2000) A novel germ line juxtamembrane Met mutation in human gastric cancer

    Oncogene 19:4947–4953.

    https://doi.org/10.1038/sj.onc.1203874

    • PubMed
    • Google Scholar
63. 1. Lee JH
    2. Gao CF
    3. Lee CC
    4. Kim MD
    5. Vande Woude GF

    (2006) An alternatively spliced form of Met receptor is tumorigenic

    Experimental & Molecular Medicine 38:565–573.

    https://doi.org/10.1038/emm.2006.66

    • PubMed
    • Google Scholar
64. 1. Lee GD
    2. Lee SE
    3. Oh DY
    4. Yu DB
    5. Jeong HM
    6. Kim J
    7. Hong S
    8. Jung HS
    9. Oh E
    10. Song JY
    11. Lee MS
    12. Kim M
    13. Jung K
    14. Kim J
    15. Shin YK
    16. Choi YL
    17. Kim HR

    (2017) MET Exon 14 skipping mutations in lung adenocarcinoma: Clinicopathologic implications and prognostic values

    Journal of Thoracic Oncology 12:1233–1246.

    https://doi.org/10.1016/j.jtho.2017.04.031

    • PubMed
    • Google Scholar
65. 1. Lefebvre J
    2. Muharram G
    3. Leroy C
    4. Kherrouche Z
    5. Montagne R
    6. Ichim G
    7. Tauszig-Delamasure S
    8. Chotteau-Lelievre A
    9. Brenner C
    10. Mehlen P
    11. Tulasne D

    (2013) Caspase-generated fragment of the Met receptor favors apoptosis via the intrinsic pathway independently of its tyrosine kinase activity

    Cell Death & Disease 4:e871.

    https://doi.org/10.1038/cddis.2013.377

    • PubMed
    • Google Scholar
66. 1. Li N
    2. Lorinczi M
    3. Ireton K
    4. Elferink LA

    (2007) Specific Grb2-mediated interactions regulate clathrin-dependent endocytosis of the cMet-tyrosine kinase

    The Journal of Biological Chemistry 282:16764–16775.

    https://doi.org/10.1074/jbc.M610835200

    • PubMed
    • Google Scholar
67. 1. Li A
    2. Yang JJ
    3. Zhang XC
    4. Zhang Z
    5. Su J
    6. Gou LY
    7. Bai Y
    8. Zhou Q
    9. Yang Z
    10. Han-Zhang H
    11. Zhong WZ
    12. Chuai S
    13. Zhang Q
    14. Xie Z
    15. Gao H
    16. Chen H
    17. Wang Z
    18. Wang Z
    19. Yang XN
    20. Wang BC
    21. Gan B
    22. Chen ZH
    23. Jiang BY
    24. Wu SP
    25. Liu SY
    26. Xu CR
    27. Wu YL

    (2017) Acquired MET Y1248H and D1246N mutations mediate resistance to MET inhibitors in non-small cell lung cancer

    Clinical Cancer Research 23:4929–4937.

    https://doi.org/10.1158/1078-0432.CCR-16-3273

    • PubMed
    • Google Scholar
68. 1. Liu S
    2. Meric-Bernstam F
    3. Parinyanitikul N
    4. Wang B
    5. Eterovic AK
    6. Zheng X
    7. Gagea M
    8. Chavez-MacGregor M
    9. Ueno NT
    10. Lei X
    11. Zhou W
    12. Nair L
    13. Tripathy D
    14. Brown PH
    15. Hortobagyi GN
    16. Chen K
    17. Mendelsohn J
    18. Mills GB
    19. Gonzalez-Angulo AM

    (2015) Functional consequence of the MET-T1010I polymorphism in breast cancer

    Oncotarget 6:2604–2614.

    https://doi.org/10.18632/oncotarget.3094

    • PubMed
    • Google Scholar
69. 1. Longati P
    2. Bardelli A
    3. Ponzetto C
    4. Naldini L
    5. Comoglio PM

    (1994)

    Tyrosines1234-1235 are critical for activation of the tyrosine kinase encoded by the MET proto-oncogene (HGF receptor)

    Oncogene 9:49–57.

    • PubMed
    • Google Scholar
70. 1. Lorenzato A
    2. Olivero M
    3. Patanè S
    4. Rosso E
    5. Oliaro A
    6. Comoglio PM
    7. Di Renzo MF

    (2002)

    Novel somatic mutations of the MET oncogene in human carcinoma metastases activating cell motility and invasion

    Cancer Research 62:7025–7030.

    • PubMed
    • Google Scholar
71. 1. Lu D
    2. Nagelberg A
    3. Chow JL
    4. Chen YT
    5. Michalchuk Q
    6. Somwar R
    7. Lockwood WW

    (2022) Met exon 14 splice-site mutations preferentially activate kras signaling to drive tumourigenesis

    Cancers 14:1378.

    https://doi.org/10.3390/cancers14061378

    • PubMed
    • Google Scholar
72. 1. Ma PC
    2. Kijima T
    3. Maulik G
    4. Fox EA
    5. Sattler M
    6. Griffin JD
    7. Johnson BE
    8. Salgia R

    (2003)

    c-MET mutational analysis in small cell lung cancer: novel juxtamembrane domain mutations regulating cytoskeletal functions

    Cancer Research 63:6272–6281.

    • PubMed
    • Google Scholar
73. 1. Ma PC
    2. Jagadeeswaran R
    3. Jagadeesh S
    4. Tretiakova MS
    5. Nallasura V
    6. Fox EA
    7. Hansen M
    8. Schaefer E
    9. Naoki K
    10. Lader A
    11. Richards W
    12. Sugarbaker D
    13. Husain AN
    14. Christensen JG
    15. Salgia R

    (2005) Functional expression and mutations of c-Met and its therapeutic inhibition with SU11274 and small interfering RNA in non-small cell lung cancer

    Cancer Research 65:1479–1488.

    https://doi.org/10.1158/0008-5472.CAN-04-2650

    • PubMed
    • Google Scholar
74. 1. Ma PC

    (2015) MET receptor juxtamembrane exon 14 alternative spliced variant: novel cancer genomic predictive biomarker

    Cancer Discovery 5:802–805.

    https://doi.org/10.1158/2159-8290.CD-15-0769

    • PubMed
    • Google Scholar
75. 1. Maina F
    2. Casagranda F
    3. Audero E
    4. Simeone A
    5. Comoglio PM
    6. Klein R
    7. Ponzetto C

    (1996) Uncoupling of Grb2 from the Met receptor in vivo reveals complex roles in muscle development

    Cell 87:531–542.

    https://doi.org/10.1016/s0092-8674(00)81372-0

    • PubMed
    • Google Scholar
76. 1. Maritano D
    2. Accornero P
    3. Bonifaci N
    4. Ponzetto C

    (2000) Two mutations affecting conserved residues in the Met receptor operate via different mechanisms

    Oncogene 19:1354–1361.

    https://doi.org/10.1038/sj.onc.1203431

    • PubMed
    • Google Scholar
77. 1. Matsumoto K
    2. Nakamura T

    (1992)

    Hepatocyte growth factor: molecular structure, roles in liver regeneration, and other biological functions

    Critical Reviews in Oncogenesis 3:27–54.

    • PubMed
    • Google Scholar
78. 1. Mendhiratta N
    2. Muraki P
    3. Sisk AE
    4. Shuch B

    (2021) Papillary renal cell carcinoma: review

    Urologic Oncology 39:327–337.

    https://doi.org/10.1016/j.urolonc.2021.04.013

    • PubMed
    • Google Scholar
79. Website

    1. Merck Global

    (2020) Tepotinib - News - Merck Global

    Accessed June 14, 2020.

    https://www.merckgroup.com/en/news/tepotinib-25-03-2020.html
80. 1. Miao YL
    2. Xu QQ

    (2019) MET Y1003S point mutation shows sensitivity to crizotinib in a patient with lung adenocarcinoma

    Lung Cancer 130:84–86.

    https://doi.org/10.1016/j.lungcan.2019.02.002

    • PubMed
    • Google Scholar
81. 1. Michieli P
    2. Basilico C
    3. Pennacchietti S
    4. Maffè A
    5. Tamagnone L
    6. Giordano S
    7. Bardelli A
    8. Comoglio PM

    (1999) Mutant Met-mediated transformation is ligand-dependent and can be inhibited by HGF antagonists

    Oncogene 18:5221–5231.

    https://doi.org/10.1038/sj.onc.1202899

    • PubMed
    • Google Scholar
82. 1. Montagne R
    2. Furlan A
    3. Kherrouche Z
    4. Tulasne D

    (2014) Le récepteur Met fête ses 30 ans

    Médecine/Sciences 30:864–873.

    https://doi.org/10.1051/medsci/20143010013

    • PubMed
    • Google Scholar
83. 1. Montagne R
    2. Baranzelli A
    3. Muharram G
    4. Catherine L
    5. Lesaffre M
    6. Vinchent A
    7. Kherrouche Z
    8. Werkmeister E
    9. Cortot AB
    10. Tulasne D

    (2017) MET receptor variant R970C favors calpain-dependent generation of a fragment promoting epithelial cell scattering

    Oncotarget 8:11268–11283.

    https://doi.org/10.18632/oncotarget.14499

    • PubMed
    • Google Scholar
84. 1. Moon YW
    2. Weil RJ
    3. Pack SD
    4. Park WS
    5. Pak E
    6. Pham T
    7. Karkera JD
    8. Kim HK
    9. Vortmeyer AO
    10. Fuller BG
    11. Zhuang Z

    (2000) Missense mutation of the MET gene detected in human glioma

    Modern Pathology 13:973–977.

    https://doi.org/10.1038/modpathol.3880177

    • PubMed
    • Google Scholar
85. 1. Nakayama M
    2. Sakai K
    3. Yamashita A
    4. Nakamura T
    5. Suzuki Y
    6. Matsumoto K

    (2013) Met/HGF receptor activation is regulated by juxtamembrane Ser985 phosphorylation in hepatocytes

    Cytokine 62:446–452.

    https://doi.org/10.1016/j.cyto.2013.04.006

    • PubMed
    • Google Scholar
86. Website

    1. Novartis

    (2020) Novartis Shows Growing Strength in Lung Cancer Innovation with New Capmatinib Investigational Data and Novel Canakinumab Clinical Trials

    Accessed June 8, 2020.

    https://www.novartis.com/news/media-releases/novartis-shows-growing-strength-lung-cancer-innovation-new-capmatinib-investigational-data-and-novel-canakinumab-clinical-trials
87. 1. Onozato R
    2. Kosaka T
    3. Kuwano H
    4. Sekido Y
    5. Yatabe Y
    6. Mitsudomi T

    (2009) Activation of MET by gene amplification or by splice mutations deleting the juxtamembrane domain in primary resected lung cancers

    Journal of Thoracic Oncology 4:5–11.

    https://doi.org/10.1097/JTO.0b013e3181913e0e

    • PubMed
    • Google Scholar
88. 1. Ou SHI
    2. Young L
    3. Schrock AB
    4. Johnson A
    5. Klempner SJ
    6. Zhu VW
    7. Miller VA
    8. Ali SM

    (2017) Emergence of preexisting met y1230c mutation as a resistance mechanism to crizotinib in nsclc with met exon 14 skipping

    Journal of Thoracic Oncology 12:137–140.

    https://doi.org/10.1016/j.jtho.2016.09.119

    • PubMed
    • Google Scholar
89. 1. Paik PK
    2. Drilon A
    3. Fan PD
    4. Yu H
    5. Rekhtman N
    6. Ginsberg MS
    7. Borsu L
    8. Schultz N
    9. Berger MF
    10. Rudin CM
    11. Ladanyi M

    (2015) Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping

    Cancer Discovery 5:842–849.

    https://doi.org/10.1158/2159-8290.CD-14-1467

    • PubMed
    • Google Scholar
90. 1. Paik PK
    2. Felip E
    3. Veillon R
    4. Sakai H
    5. Cortot AB
    6. Garassino MC
    7. Mazieres J
    8. Viteri S
    9. Senellart H
    10. Van Meerbeeck J
    11. Raskin J
    12. Reinmuth N
    13. Conte P
    14. Kowalski D
    15. Cho BC
    16. Patel JD
    17. Horn L
    18. Griesinger F
    19. Han JY
    20. Kim YC
    21. Chang GC
    22. Tsai CL
    23. Yang JCH
    24. Chen YM
    25. Smit EF
    26. van der Wekken AJ
    27. Kato T
    28. Juraeva D
    29. Stroh C
    30. Bruns R
    31. Straub J
    32. Johne A
    33. Scheele J
    34. Heymach JV
    35. Le X

    (2020) Tepotinib in non-small-cell lung cancer with MET Exon 14 skipping mutations

    The New England Journal of Medicine 383:931–943.

    https://doi.org/10.1056/NEJMoa2004407

    • PubMed
    • Google Scholar
91. 1. Park WS
    2. Dong SM
    3. Kim SY
    4. Na EY
    5. Shin MS
    6. Pi JH
    7. Kim BJ
    8. Bae JH
    9. Hong YK
    10. Lee KS
    11. Lee SH
    12. Yoo NJ
    13. Jang JJ
    14. Pack S
    15. Zhuang Z
    16. Schmidt L
    17. Zbar B
    18. Lee JY

    (1999)

    Somatic mutations in the kinase domain of the Met/hepatocyte growth factor receptor gene in childhood hepatocellular carcinomas

    Cancer Research 59:307–310.

    • PubMed
    • Google Scholar
92. 1. Peschard P
    2. Fournier TM
    3. Lamorte L
    4. Naujokas MA
    5. Band H
    6. Langdon WY
    7. Park M

    (2001) Mutation of the c-Cbl TKB domain binding site on the Met receptor tyrosine kinase converts it into a transforming protein

    Molecular Cell 8:995–1004.

    https://doi.org/10.1016/s1097-2765(01)00378-1

    • PubMed
    • Google Scholar
93. Website

    1. Pfizer

    (2020) Pfizer’s XALKORI (crizotinib) Receives FDA Breakthrough Therapy Designation in Two New Indications

    Accessed June 8, 2020.

    https://www.pfizer.com/news/press-release/press-release-detail/pfizer_s_xalkori_crizotinib_receives_fda_breakthrough_therapy_designation_in_two_new_indications-0
94. 1. Pilotto S
    2. Gkountakos A
    3. Carbognin L
    4. Scarpa A
    5. Tortora G
    6. Bria E

    (2017) MET exon 14 juxtamembrane splicing mutations: clinical and therapeutical perspectives for cancer therapy

    Annals of Translational Medicine 5:2.

    https://doi.org/10.21037/atm.2016.12.33

    • PubMed
    • Google Scholar
95. 1. Ponzetto C
    2. Giordano S
    3. Peverali F
    4. Della Valle G
    5. Abate ML
    6. Vaula G
    7. Comoglio PM

    (1991)

    c-met is amplified but not mutated in a cell line with an activated met tyrosine kinase

    Oncogene 6:553–559.

    • PubMed
    • Google Scholar
96. 1. Ponzetto C
    2. Bardelli A
    3. Maina F
    4. Longati P
    5. Panayotou G
    6. Dhand R
    7. Waterfield MD
    8. Comoglio PM

    (1993) A novel recognition motif for phosphatidylinositol 3-kinase binding mediates its association with the hepatocyte growth factor/scatter factor receptor

    Molecular and Cellular Biology 13:4600–4608.

    https://doi.org/10.1128/mcb.13.8.4600-4608.1993

    • PubMed
    • Google Scholar
97. 1. Ponzetto C
    2. Bardelli A
    3. Zhen Z
    4. Maina F
    5. dalla Zonca P
    6. Giordano S
    7. Graziani A
    8. Panayotou G
    9. Comoglio PM

    (1994) A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family

    Cell 77:261–271.

    https://doi.org/10.1016/0092-8674(94)90318-2

    • PubMed
    • Google Scholar
98. 1. Recondo G
    2. Bahcall M
    3. Spurr LF
    4. Che J
    5. Ricciuti B
    6. Leonardi GC
    7. Lo YC
    8. Li YY
    9. Lamberti G
    10. Nguyen T
    11. Milan MSD
    12. Venkatraman D
    13. Umeton R
    14. Paweletz CP
    15. Albayrak A
    16. Cherniack AD
    17. Price KS
    18. Fairclough SR
    19. Nishino M
    20. Sholl LM
    21. Oxnard GR
    22. Jänne PA
    23. Awad MM

    (2020) Molecular mechanisms of acquired resistance to met tyrosine kinase inhibitors in patients with met exon 14-mutant nsclc

    Clinical Cancer Research 26:2615–2625.

    https://doi.org/10.1158/1078-0432.CCR-19-3608

    • PubMed
    • Google Scholar
99. 1. Rhoades Smith KE
    2. Bilen MA

    (2019) A review of papillary renal cell carcinoma and met inhibitors

    Kidney Cancer 3:151–161.

    https://doi.org/10.3233/KCA-190058

    • PubMed
    • Google Scholar
100. Preprint

     1. Rotow JK
     2. Gui P
     3. Wu W
     4. Raymond VM
     5. Lanman RB
     6. Kaye FJ

     (2018) Co-occurring genetic alterations in the ras pathway promote resistance to met inhibitor treatment in non-small cell lung cancer with a met exon 14 skipping mutation

     bioRxiv.

     https://doi.org/10.1101/374181

     • Google Scholar
101. 1. Rubin JS
     2. Bottaro DP
     3. Aaronson SA

     (1993) Hepatocyte growth factor/scatter factor and its receptor, the c-met proto-oncogene product

     Biochimica et Biophysica Acta 1155:357–371.

     https://doi.org/10.1016/0304-419x(93)90015-5

     • PubMed
     • Google Scholar
102. 1. Schmidt C
     2. Bladt F
     3. Goedecke S
     4. Brinkmann V
     5. Zschiesche W
     6. Sharpe M
     7. Gherardi E
     8. Birchmeier C

     (1995) Scatter factor/hepatocyte growth factor is essential for liver development

     Nature 373:699–702.

     https://doi.org/10.1038/373699a0

     • PubMed
     • Google Scholar
103. 1. Schmidt L
     2. Duh FM
     3. Chen F
     4. Kishida T
     5. Glenn G
     6. Choyke P
     7. Scherer SW
     8. Zhuang Z
     9. Lubensky I
     10. Dean M
     11. Allikmets R
     12. Chidambaram A
     13. Bergerheim UR
     14. Feltis JT
     15. Casadevall C
     16. Zamarron A
     17. Bernues M
     18. Richard S
     19. Lips CJ
     20. Walther MM
     21. Tsui LC
     22. Geil L
     23. Orcutt ML
     24. Stackhouse T
     25. Lipan J
     26. Slife L
     27. Brauch H
     28. Decker J
     29. Niehans G
     30. Hughson MD
     31. Moch H
     32. Storkel S
     33. Lerman MI
     34. Linehan WM
     35. Zbar B

     (1997) Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas

     Nature Genetics 16:68–73.

     https://doi.org/10.1038/ng0597-68

     • PubMed
     • Google Scholar
104. 1. Schmidt L
     2. Junker K
     3. Nakaigawa N
     4. Kinjerski T
     5. Weirich G
     6. Miller M
     7. Lubensky I
     8. Neumann HP
     9. Brauch H
     10. Decker J
     11. Vocke C
     12. Brown JA
     13. Jenkins R
     14. Richard S
     15. Bergerheim U
     16. Gerrard B
     17. Dean M
     18. Linehan WM
     19. Zbar B

     (1999) Novel mutations of the MET proto-oncogene in papillary renal carcinomas

     Oncogene 18:2343–2350.

     https://doi.org/10.1038/sj.onc.1202547

     • PubMed
     • Google Scholar
105. 1. Schöffski P
     2. Wozniak A
     3. Escudier B
     4. Rutkowski P
     5. Anthoney A
     6. Bauer S
     7. Sufliarsky J
     8. van Herpen C
     9. Lindner LH
     10. Grünwald V
     11. Zakotnik B
     12. Lerut E
     13. Debiec-Rychter M
     14. Marréaud S
     15. Lia M
     16. Raveloarivahy T
     17. Collette S
     18. Albiges L

     (2017) Crizotinib achieves long-lasting disease control in advanced papillary renal-cell carcinoma type 1 patients with MET mutations or amplification: EORTC 90101 CREATE trial

     European Journal of Cancer 87:147–163.

     https://doi.org/10.1016/j.ejca.2017.10.014

     • PubMed
     • Google Scholar
106. 1. Schrock AB
     2. Frampton GM
     3. Suh J
     4. Chalmers ZR
     5. Rosenzweig M
     6. Erlich RL
     7. Halmos B
     8. Goldman J
     9. Forde P
     10. Leuenberger K
     11. Peled N
     12. Kalemkerian GP
     13. Ross JS
     14. Stephens PJ
     15. Miller VA
     16. Ali SM
     17. Ou SHI

     (2016) Characterization of 298 patients with lung cancer harboring met exon 14 skipping alterations

     Journal of Thoracic Oncology 11:1493–1502.

     https://doi.org/10.1016/j.jtho.2016.06.004

     • PubMed
     • Google Scholar
107. 1. Sebai M
     2. Tulasne D
     3. Caputo SM
     4. Verkarre V
     5. Fernandes M
     6. Guérin C
     7. Reinhart F
     8. Adams S
     9. Maugard C
     10. Caron O
     11. Guillaud-Bataille M
     12. Berthet P
     13. Bignon YJ
     14. Bressac-de Paillerets B
     15. Burnichon N
     16. Chiesa J
     17. Giraud S
     18. Lejeune S
     19. Limacher JM
     20. de Pauw A
     21. Stoppa-Lyonnet D
     22. Zattara-Cannoni H
     23. Deveaux S
     24. Lidereau R
     25. Richard S
     26. Rouleau E

     (2022) Novel germline MET pathogenic variants in French patients with papillary renal cell carcinomas type I

     Human Mutation 43:316–327.

     https://doi.org/10.1002/humu.24313

     • PubMed
     • Google Scholar
108. 1. Seiwert TY
     2. Jagadeeswaran R
     3. Faoro L
     4. Janamanchi V
     5. Nallasura V
     6. El Dinali M
     7. Yala S
     8. Kanteti R
     9. Cohen EEW
     10. Lingen MW
     11. Martin L
     12. Krishnaswamy S
     13. Klein-Szanto A
     14. Christensen JG
     15. Vokes EE
     16. Salgia R

     (2009) The MET receptor tyrosine kinase is a potential novel therapeutic target for head and neck squamous cell carcinoma

     Cancer Research 69:3021–3031.

     https://doi.org/10.1158/0008-5472.CAN-08-2881

     • PubMed
     • Google Scholar
109. 1. Stella MC
     2. Comoglio PM

     (1999) HGF: A multifunctional growth factor controlling cell scattering

     The International Journal of Biochemistry & Cell Biology 31:1357–1362.

     https://doi.org/10.1016/s1357-2725(99)00089-8

     • PubMed
     • Google Scholar
110. 1. Stella GM
     2. Benvenuti S
     3. Gramaglia D
     4. Scarpa A
     5. Tomezzoli A
     6. Cassoni P
     7. Senetta R
     8. Venesio T
     9. Pozzi E
     10. Bardelli A
     11. Comoglio PM

     (2011) MET mutations in cancers of unknown primary origin (CUPs)

     Human Mutation 32:44–50.

     https://doi.org/10.1002/humu.21374

     • PubMed
     • Google Scholar
111. 1. Stransky N
     2. Cerami E
     3. Schalm S
     4. Kim JL
     5. Lengauer C

     (2014) The landscape of kinase fusions in cancer

     Nature Communications 5:4846.

     https://doi.org/10.1038/ncomms5846

     • PubMed
     • Google Scholar
112. 1. Suárez C
     2. Larkin JMG
     3. Patel P
     4. Valderrama BP
     5. Rodriguez-Vida A
     6. Glen H
     7. Thistlethwaite F
     8. Ralph C
     9. Srinivasan G
     10. Mendez-Vidal MJ
     11. Hartmaier R
     12. Markovets A
     13. Prendergast A
     14. Szabados B
     15. Mousa K
     16. Powles T

     (2023) Phase ii study investigating the safety and efficacy of savolitinib and durvalumab in metastatic papillary renal cancer (calypso)

     Journal of Clinical Oncology 41:2493–2502.

     https://doi.org/10.1200/JCO.22.01414

     • PubMed
     • Google Scholar
113. 1. Suzawa K
     2. Offin M
     3. Lu D
     4. Kurzatkowski C
     5. Vojnic M
     6. Smith RS
     7. Sabari JK
     8. Tai H
     9. Mattar M
     10. Khodos I
     11. de Stanchina E
     12. Rudin CM
     13. Kris MG
     14. Arcila ME
     15. Lockwood WW
     16. Drilon A
     17. Ladanyi M
     18. Somwar R

     (2019) Activation of kras mediates resistance to targeted therapy in met exon 14–mutant non–small cell lung cancer

     Clinical Cancer Research 25:1248–1260.

     https://doi.org/10.1158/1078-0432.CCR-18-1640

     • Google Scholar
114. 1. Tamagnone L
     2. Comoglio PM

     (1997) Control of invasive growth by hepatocyte growth factor (HGF) and related scatter factors

     Cytokine & Growth Factor Reviews 8:129–142.

     https://doi.org/10.1016/s1359-6101(97)00007-5

     • PubMed
     • Google Scholar
115. 1. Tanimura S
     2. Asato K
     3. Fujishiro S
     4. Kohno M

     (2003) Specific blockade of the ERK pathway inhibits the invasiveness of tumor cells: down-regulation of matrix metalloproteinase-3/-9/-14 and CD44

     Biochemical and Biophysical Research Communications 304:801–806.

     https://doi.org/10.1016/s0006-291x(03)00670-3

     • PubMed
     • Google Scholar
116. 1. Tengs T
     2. Lee JC
     3. Paez JG
     4. Zhao X
     5. LaFramboise T
     6. Giannoukos G
     7. Thomas RK

     (2006) A transforming MET mutation discovered in non-small cell lung cancer using microarray-based resequencing

     Cancer Letters 239:227–233.

     https://doi.org/10.1016/j.canlet.2005.08.007

     • PubMed
     • Google Scholar
117. 1. Togashi Y
     2. Mizuuchi H
     3. Tomida S
     4. Terashima M
     5. Hayashi H
     6. Nishio K
     7. Mitsudomi T

     (2015) MET gene exon 14 deletion created using the CRISPR/Cas9 system enhances cellular growth and sensitivity to a MET inhibitor

     Lung Cancer 90:590–597.

     https://doi.org/10.1016/j.lungcan.2015.10.020

     • PubMed
     • Google Scholar
118. 1. Tong CYK
     2. Hui ABY
     3. Yin XL
     4. Pang JCS
     5. Zhu XL
     6. Poon WS
     7. Ng HK

     (2004) Detection of oncogene amplifications in medulloblastomas by comparative genomic hybridization and array-based comparative genomic hybridization

     Journal of Neurosurgery 100:187–193.

     https://doi.org/10.3171/ped.2004.100.2.0187

     • PubMed
     • Google Scholar
119. 1. Tovar EA
     2. Graveel CR

     (2017) MET in human cancer: germline and somatic mutations

     Annals of Translational Medicine 5:205.

     https://doi.org/10.21037/atm.2017.03.64

     • PubMed
     • Google Scholar
120. 1. Tulasne D
     2. Deheuninck J
     3. Lourenco FC
     4. Lamballe F
     5. Ji Z
     6. Leroy C
     7. Puchois E
     8. Moumen A
     9. Maina F
     10. Mehlen P
     11. Fafeur V

     (2004) Proapoptotic function of the MET tyrosine kinase receptor through caspase cleavage

     Molecular and Cellular Biology 24:10328–10339.

     https://doi.org/10.1128/MCB.24.23.10328-10339.2004

     • PubMed
     • Google Scholar
121. 1. Tyner JW
     2. Fletcher LB
     3. Wang EQ
     4. Yang WF
     5. Rutenberg-Schoenberg ML
     6. Beadling C
     7. Mori M
     8. Heinrich MC
     9. Deininger MW
     10. Druker BJ
     11. Loriaux MM

     (2010) MET receptor sequence variants R970C and T992I lack transforming capacity

     Cancer Research 70:6233–6237.

     https://doi.org/10.1158/0008-5472.CAN-10-0429

     • PubMed
     • Google Scholar
122. 1. Uchikawa E
     2. Chen Z
     3. Xiao GY
     4. Zhang X
     5. Bai XC

     (2021) Structural basis of the activation of c-MET receptor

     Nature Communications 12:4074.

     https://doi.org/10.1038/s41467-021-24367-3

     • PubMed
     • Google Scholar
123. 1. Uehara Y
     2. Minowa O
     3. Mori C
     4. Shiota K
     5. Kuno J
     6. Noda T
     7. Kitamura N

     (1995) Placental defect and embryonic lethality in mice lacking hepatocyte growth factor/scatter factor

     Nature 373:702–705.

     https://doi.org/10.1038/373702a0

     • PubMed
     • Google Scholar
124. 1. Ujiie H
     2. Tomida M
     3. Akiyama H
     4. Nakajima Y
     5. Okada D
     6. Yoshino N
     7. Takiguchi Y
     8. Tanzawa H

     (2012)

     Serum hepatocyte growth factor and interleukin-6 are effective prognostic markers for non-small cell lung cancer

     Anticancer Research 32:3251–3258.

     • PubMed
     • Google Scholar
125. 1. Umeki K
     2. Shiota G
     3. Kawasaki H

     (1999) Clinical significance of c-met oncogene alterations in human colorectal cancer

     Oncology 56:314–321.

     https://doi.org/10.1159/000011985

     • PubMed
     • Google Scholar
126. 1. Vieira T
     2. Antoine M
     3. Ruppert AM
     4. Fallet V
     5. Duruisseaux M
     6. Giroux Leprieur E
     7. Poulot V
     8. Rabbe N
     9. Sclick L
     10. Beau-Faller M
     11. Lacave R
     12. Lavole A
     13. Cadranel J
     14. Wislez M

     (2014) Blood vessel invasion is a major feature and a factor of poor prognosis in sarcomatoid carcinoma of the lung

     Lung Cancer 85:276–281.

     https://doi.org/10.1016/j.lungcan.2014.06.004

     • PubMed
     • Google Scholar
127. 1. Waqar SN
     2. Morgensztern D
     3. Sehn J

     (2015) Met mutation associated with responsiveness to crizotinib

     Journal of Thoracic Oncology 10:e29–e31.

     https://doi.org/10.1097/JTO.0000000000000478

     • PubMed
     • Google Scholar
128. 1. Weidner KM
     2. Sachs M
     3. Riethmacher D
     4. Birchmeier W

     (1995) Mutation of juxtamembrane tyrosine residue 1001 suppresses loss-of-function mutations of the met receptor in epithelial cells

     PNAS 92:2597–2601.

     https://doi.org/10.1073/pnas.92.7.2597

     • PubMed
     • Google Scholar
129. 1. Woolf AS
     2. Kolatsi-Joannou M
     3. Hardman P
     4. Andermarcher E
     5. Moorby C
     6. Fine LG
     7. Jat PS
     8. Noble MD
     9. Gherardi E

     (1995) Roles of hepatocyte growth factor/scatter factor and the met receptor in the early development of the metanephros

     The Journal of Cell Biology 128:171–184.

     https://doi.org/10.1083/jcb.128.1.171

     • PubMed
     • Google Scholar
130. 1. Yan SB
     2. Um SL
     3. Peek VL
     4. Stephens JR
     5. Zeng W
     6. Konicek BW
     7. Liu L
     8. Manro JR
     9. Wacheck V
     10. Walgren RA

     (2018) MET-targeting antibody (emibetuzumab) and kinase inhibitor (merestinib) as single agent or in combination in a cancer model bearing MET exon 14 skipping

     Investigational New Drugs 36:536–544.

     https://doi.org/10.1007/s10637-017-0545-x

     • PubMed
     • Google Scholar
131. 1. Yang Y
     2. Spitzer E
     3. Meyer D
     4. Sachs M
     5. Niemann C
     6. Hartmann G
     7. Weidner KM
     8. Birchmeier C
     9. Birchmeier W

     (1995) Sequential requirement of hepatocyte growth factor and neuregulin in the morphogenesis and differentiation of the mammary gland

     The Journal of Cell Biology 131:215–226.

     https://doi.org/10.1083/jcb.131.1.215

     • PubMed
     • Google Scholar
132. 1. Yang CQ
     2. Li W
     3. Li SQ
     4. Li J
     5. Li YW
     6. Kong SX
     7. Liu RM
     8. Wang SM
     9. Lv WM

     (2014) MCP-1 stimulates MMP-9 expression via ERK 1/2 and p38 MAPK signaling pathways in human aortic smooth muscle cells

     Cellular Physiology and Biochemistry 34:266–276.

     https://doi.org/10.1159/000362997

     • PubMed
     • Google Scholar
133. 1. Yao Y
     2. Yang H
     3. Zhu B
     4. Wang S
     5. Pang J
     6. Wu X
     7. Xu Y
     8. Zhang J
     9. Zhang J
     10. Ou Q
     11. Tian H
     12. Zhao Z

     (2023) Mutations in the MET tyrosine kinase domain and resistance to tyrosine kinase inhibitors in non-small-cell lung cancer

     Respiratory Research 24:28.

     https://doi.org/10.1186/s12931-023-02329-1

     • PubMed
     • Google Scholar
134. 1. Zaffaroni D
     2. Spinola M
     3. Galvan A
     4. Falvella FS
     5. Pazzaglia S
     6. Saran A
     7. Mancuso MT
     8. Galbiati F
     9. Pignatiello C
     10. Cabrera W
     11. Ibanez O
     12. Manenti G
     13. Dragani TA

     (2005) Met proto-oncogene juxtamembrane rare variations in mouse and humans: differential effects of Arg and Cys alleles on mouse lung tumorigenesis

     Oncogene 24:1084–1090.

     https://doi.org/10.1038/sj.onc.1208324

     • PubMed
     • Google Scholar
135. 1. Zhang Y
     2. Yin J
     3. Peng F

     (2017) Acquired resistance to crizotinib in advanced lung adenocarcinoma with MET exon 14 skipping

     Lung Cancer 113:69–71.

     https://doi.org/10.1016/j.lungcan.2017.09.006

     • PubMed
     • Google Scholar

Author details

1. Célia Guérin

   Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020 – UMR1277 - Canther – Cancer Heterogeneity, Plasticity and Resistance to Therapies, Lille, France

   Contribution

   Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

2. David Tulasne

   Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020 – UMR1277 - Canther – Cancer Heterogeneity, Plasticity and Resistance to Therapies, Lille, France

   Contribution

   Writing – original draft, Writing – review and editing

   For correspondence

   david.tulasne@cnrs.fr

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-6764-7242

• 131

  views

• 31

  downloads

• 0

  citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.