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

Sordella, R.; Pal, D.; Safaric Tepes, P.; Lindsted, T.; Ibarra, I.; Lujambio, A.; Jimenez Sabinina, V.; Senturk, S.; Miller, M.; Korimerla, N.; Huang, J.; Glassman, L.; Lee, P.; Zeltsman, D.; Hyman, K.; Esposito, M.; Hannon, G.

doi:10.1101/2021.01.06.425631

bioRxiv · 10.1101/2021.01.06.425631

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

Sordella, R.·Pal, D.·Safaric Tepes, P.·Lindsted, T.·Ibarra, I.·Lujambio, A.·Jimenez Sabinina, V.·Senturk, S.·Miller, M.·Korimerla, N.·Huang, J.·Glassman, L.·Lee, P.·Zeltsman, D.·Hyman, K.·Esposito, M.·Hannon, G.

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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-naive 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.

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Sordella, R., Pal, D., Safaric Tepes, P., Lindsted, T., Ibarra, I., Lujambio, A., Jimenez Sabinina, V., Senturk, S., Miller, M., Korimerla, N., Huang, J., Glassman, L., Lee, P., Zeltsman, D., Hyman, K., Esposito, M., Hannon, G.. 2021-01-07. An epigenetic switch regulates the ontogeny of AXL positive/EGFR-TKI resistant cells by modulating miR-335 expression. https://doi.org/10.1101/2021.01.06.425631

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