An epigenetic switch regulates the ontogeny of AXL positive/EGFR-TKI resistant cells by modulating miR-335 expression.

Safaric Tepes, Polona, Pal, Debjani, Lindsted, Trine, Ibarra, Ingrid, Lujambio, Amaia, Jimenez Sabinina, Vilma, Senturk, Serif, Miller, Madison, Korimerla, Navya, Huang, Jiahao, Glassman, Lawrence, Lee, Paul, Zeltsman, David, Hyman, Kevin, Esposito, Michael, Hannon, Greg, Sordella, Raffaella (July 2021) An epigenetic switch regulates the ontogeny of AXL positive/EGFR-TKI resistant cells by modulating miR-335 expression. eLife, 10. ISSN 2050-084X

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Abstract

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.

Item Type:	Paper
Subjects:	diseases & disorders > cancer > drugs and therapies diseases & disorders > cancer > cancer types > lung cancer
CSHL Authors:	Pal, Debjani Lindsted, Trine Ibarra, Ingrid Senturk, Serif Miller, Madison Hannon, Gregory J. Sordella, Raffaella
Communities:	CSHL labs > Sordella lab School of Biological Sciences > Publications
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	13 July 2021
Date Deposited:	14 Jul 2021 14:52
Last Modified:	01 Jun 2022 17:15
PMCID:	PMC8285107
URI:	https://repository.cshl.edu/id/eprint/40291

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