Despite current advancements in research and therapeutics, lung cancer remains the leading cause of cancer-related mortality worldwide. This is mainly due to the resistance that patients develop against chemotherapeutic agents over the course of treatment. In the context of non-small cell lung cancers (NSCLC) harboring EGFR oncogenic mutations, augmented levels of AXL and GAS6 have been found to drive resistance to EGFR tyrosine kinase inhibitors such as Erlotinib and Osimertinib in certain tumors with mesenchymal-like features. By studying the ontogeny of AXL-positive cells, we have identified a novel non-genetic mechanism of drug resistance based on cell-state transition. We demonstrate that AXL-positive cells are already present as a sub-population of cancer cells in Erlotinib-naïve tumors and tumor-derived cell lines, and that the expression of AXL is regulated through a stochastic mechanism centered on the epigenetic regulation of miR-335. The existence of a cell-intrinsic program through which AXL-positive/Erlotinib-resistant cells emerge infers the need of treating tumors harboring EGFR-oncogenic mutations upfront with combinatorial treatments targeting both AXL-negative and AXL-positive cancer cells.
The data generated or analyzed during this study are included in the manuscript and supporting files.
No external funding was received for this work.
Human subjects: The collection of human lung tissue samples and blood for this study was covered by Northwell Health/Cold Spring Harbor Laboratory IRB #TDP-TAP 1607 (Raffaella Sordella/10/11/16 ). The samples were acquired from patients already undergoing thoracic procedures (e.g. surgical tumor resection, biopsy) at Huntington Hospital. All study participants provided informed consent for the use of their lung tissue and blood for research purposes. Participants were informed of study aims, the potential risks and benefits of participation, and that any discoveries facilitated by the analysis of their tissues might be published. The participants were informed that their names would not be associated their samples in any publication or presentation of research findings.
- Michael R Green, Howard Hughes Medical Institute, University of Massachusetts Medical School, United States
© 2021, Safaric Tepes et al.
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