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

[img] PDF
2021.Tepes.mir335.pdf

Download (59MB)
URL: https://www.ncbi.nlm.nih.gov/pubmed/34254585
DOI: 10.7554/eLife.66109

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:
Communities: CSHL labs > Sordella lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 13 July 2021
Date Deposited: 14 Jul 2021 14:52
Last Modified: 21 Jul 2021 13:27
PMCID: PMC8285107
URI: https://repository.cshl.edu/id/eprint/40291

Actions (login required)

Administrator's edit/view item Administrator's edit/view item
CSHL HomeAbout CSHLResearchEducationNews & FeaturesCampus & Public EventsCareersGiving