An epigenetic switch regulates the ontogeny of AXL-positive/EGFR-TKI resistant cells by modulating miR-335 expression
- Abstract:
- ABSTRACT Lung cancer remains the leading cause of cancer-related mortality worldwide, despite current advancements in research and therapeutics. Many patients diagnosed with lung cancer will develop resistance to chemotherapeutic agents. 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 Erlotinib resistance 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.
- Authors:
- D Pal, PS Tepes, T Lindsted, I Ibarra, A Lujambio, VJ Sabinina, S Senturk, M Miller, N Korimerla, J Huang, L Glassman, P Lee, D Zeltsman, K Hyman, M Esposito, GJ Hannon, R Sordella
- Publication date:
- 10th Jan 2021
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- DOI