Multi-targeted therapy resistance via drug-induced secretome fucosylation
- Seoul National University, Republic of Korea
- Korea Advanced Institute of Science and Technology, Republic of Korea
- Max Planck Institute of Biochemistry, Germany
- Seoul National University Hospital, Republic of Korea
- Seoul National University Bundang Hospital, Republic of Korea
Abstract
Cancer secretome is a reservoir for aberrant glycosylation. How therapies alter this post- translational cancer hallmark and the consequences thereof remain elusive. Here we show that an elevated secretome fucosylation is a pan-cancer signature of both response and resistance to multiple targeted therapies. Large-scale pharmacogenomics revealed that fucosylation genes display widespread association with resistance to these therapies. In cancer cell cultures, xenograft mouse models, and patients, targeted kinase inhibitors distinctively induced core fucosylation of secreted proteins less than 60 kDa. Label-free proteomics of N-glycoproteomes identified fucosylation of the antioxidant PON1 as a critical component of the therapy-induced secretome (TIS). N-glycosylation of TIS and target core fucosylation of PON1 are mediated by the fucose salvage-FUT8-SLC35C1 axis with PON3 directly modulating GDP-Fuc transfer on PON1 scaffolds. Core fucosylation in the Golgi impacts PON1 stability and folding prior to secretion, promoting a more degradation-resistant PON1. Global and PON1-specific secretome de-N-glycosylation both limited the expansion of resistant clones in a tumor regression model. We defined the resistance-associated transcription factors (TFs) and genes modulated by the N-glycosylated TIS via a focused and transcriptome-wide analyses. These genes characterize the oxidative stress, inflammatory niche, and unfolded protein response as important factors for this modulation. Our findings demonstrate that core fucosylation is a common modification indirectly induced by targeted therapies that paradoxically promotes resistance.
Data availability
All sequencing data produced for this publication has been deposited to the NCBI Gene Expression Omnibus (GEO) database under the accession number GSE160205. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD022240. Source Data 1 contains raw images of blots and gels. Other data associated with this study are present in the paper, Supplementary Materials, or source data files. Additional data related to this paper may be requested from M.B.D.A., Yoosik K., or J.Y.C. Reagents, and cell lines described here are accessible through a materials transfer agreement.
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Widespread multi-targeted therapy resistance via drug-induced secretome fucosylationNCBI Gene Expression Omnibus, GSE160205.
Article and author information
Author details
Roben D Delos Reyes
Funding
Korea Advanced Institute of Science and Technology (N11190234)
- Yoosik Kim
National Research Foundation of Korea (NRF-2019R1C1C1006672)
- Yoosik Kim
National Research Foundation of Korea (NRF-2018R1A6A3A01012494)
- Pilnam Kim
National Research Foundation of Korea (NRF-2016M3A9B6026771)
- Je-Yoel Cho
National Research Foundation of Korea (NRF-2021R1A5A1033157)
- Je-Yoel Cho
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: All human blood and tissues from three cohorts of patients diagnosed to have lung adenocarcinoma or squamous cell carcinoma or breast carcinoma were collected and analyzed with approved protocols in accordance with the ethical requirements and regulations of the Institutional Review Board of Seoul National University Hospital after securing written informed consent (IRB Nos. 1104-086-359 and B-1201/143-003).
Copyright
© 2023, Aldonza et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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