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

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Safaric Tepes, Polona  ORCID logo
Pal, Debjani 
Lindsted, Trine 
Ibarra, Ingrid 

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.

AXL, cancer biology, epigenetics, erlotinib-resistant, human, lung cancer, Acrylamides, Aniline Compounds, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Drug Resistance, Neoplasm, Epigenesis, Genetic, ErbB Receptors, Erlotinib Hydrochloride, Humans, Intercellular Signaling Peptides and Proteins, Lung Neoplasms, MicroRNAs, Mutation, Protein Kinase Inhibitors, Proto-Oncogene Proteins, RNA, Messenger, Receptor Protein-Tyrosine Kinases
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eLife Sciences Publications, Ltd