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

Polona Safaric Tepes,Trine Lindsted,Debjani Pal,Lawrence Glassman,Navya Korimerla,Vilma Jimenez Sabinina,Amaia Lujambio,Ingrid Ibarra,Paul Lee,Gregory J Hannon,Raffaella Sordella,Madison Miller,David Zeltsman,Jiahao Huang,Serif Senturk,Kevin Hyman,Michael Esposito

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 subpopulation 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.

Highlights

Each year, more than a million patients worldwide are diagnosed with non–small cell lung cancer (NSCLC) (Brose et al, 2002; Samuels et al, 2004; Stephens et al, 2004; Haber et al, 2005; Bean et al, 2007; Pillai and Ramalingam, 2012)
We showed that the generation of AXL-positive cells is centered on the methylation of a specific CpG island present in the promoter of mesoderm-specific transcript homolog (MEST), a gene that contains the miRNA miR-335 in its second intron
It has been shown that when non–small cell lung cancer (NSCLC)-derived cell lines harboring EGFRoncogenic mutations are exposed to EGFR TKis like Erlotinib, populations of AXL-positive/Erlotinibresistant cells emerge with features similar to those observed in tumors that have developed Erlotinib treatment resistance in patients (Zhang et al, 2012)

Summary

Introduction

More than a million patients worldwide are diagnosed with non–small cell lung cancer (NSCLC) (Brose et al, 2002; Samuels et al, 2004; Stephens et al, 2004; Haber et al, 2005; Bean et al, 2007; Pillai and Ramalingam, 2012). In 2014, the discovery that EGFR-oncogenic mutations were present in 15–30% of NSCLC patients and that the vast majority of patients harboring such mutations are sensitive to treatment with EGFR inhibitors (TKi) such as Erlotinib and Safaric Tepes, Pal, et al eLife 2021;10:e66109. Gefitinib was a critical breakthrough (Lynch et al, 2004; Paez et al, 2004). The identification of these actionable EGFR-oncogenic mutations revolutionized the management of NSCLC tumors from a predominantly clinical-pathological to a genotype-directed classification and therapeutic approach. Within a year of treatment with EGFR TKIs, almost all patients experience relapse (Bell et al, 2005)

Methods

Results

Conclusion