An epigenetic switch regulates the ontogeny of AXL-positive/EGFR-TKi-resistant cells by modulating miR-335 expression
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 cance...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-07-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/66109 |
| _version_ | 1818018700566986752 |
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| author | Polona Safaric Tepes Debjani Pal Trine Lindsted Ingrid Ibarra Amaia Lujambio Vilma Jimenez Sabinina Serif Senturk Madison Miller Navya Korimerla Jiahao Huang Lawrence Glassman Paul Lee David Zeltsman Kevin Hyman Michael Esposito Gregory J Hannon Raffaella Sordella |
| author_facet | Polona Safaric Tepes Debjani Pal Trine Lindsted Ingrid Ibarra Amaia Lujambio Vilma Jimenez Sabinina Serif Senturk Madison Miller Navya Korimerla Jiahao Huang Lawrence Glassman Paul Lee David Zeltsman Kevin Hyman Michael Esposito Gregory J Hannon Raffaella Sordella |
| author_sort | Polona Safaric Tepes |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-14T07:43:32Z |
| format | Article |
| id | doaj.art-8f753d647a7d4f28ad16d9538172ef03 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-14T07:43:32Z |
| publishDate | 2021-07-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-8f753d647a7d4f28ad16d9538172ef032022-12-22T02:05:25ZengeLife Sciences Publications LtdeLife2050-084X2021-07-011010.7554/eLife.66109An epigenetic switch regulates the ontogeny of AXL-positive/EGFR-TKi-resistant cells by modulating miR-335 expressionPolona Safaric Tepes0https://orcid.org/0000-0002-5833-739XDebjani Pal1Trine Lindsted2Ingrid Ibarra3Amaia Lujambio4https://orcid.org/0000-0002-2798-1481Vilma Jimenez Sabinina5Serif Senturk6Madison Miller7Navya Korimerla8Jiahao Huang9Lawrence Glassman10Paul Lee11David Zeltsman12Kevin Hyman13Michael Esposito14Gregory J Hannon15Raffaella Sordella16https://orcid.org/0000-0001-9745-1227Cold Spring Harbor Laboratory, Cold Spring Harbor, United States; Faculty of Pharmacy University of Ljubljana, Ljubljana, SloveniaCold Spring Harbor Laboratory, Cold Spring Harbor, United States; Graduate Program in Molecular and Cellular Biology, Stony Brook University, Stony Brook, New York, United StatesCold Spring Harbor Laboratory, Cold Spring Harbor, United StatesCold Spring Harbor Laboratory, Cold Spring Harbor, United StatesIcahn School of Medicine at Mount Sinai, Hess Center for Science and Medicine, New York, United StatesCold Spring Harbor Laboratory, Cold Spring Harbor, United StatesCold Spring Harbor Laboratory, Cold Spring Harbor, United StatesCold Spring Harbor Laboratory, Cold Spring Harbor, United StatesCold Spring Harbor Laboratory, Cold Spring Harbor, United States; Graduate Program in Biomedical Engineering, Stony Brook University, New York, United StatesCold Spring Harbor Laboratory, Cold Spring Harbor, United StatesNorthwell Health Long Island, Jewish Medical Center, New York, United StatesNorthwell Health Long Island, Jewish Medical Center, New York, United StatesNorthwell Health Long Island, Jewish Medical Center, New York, United StatesNorthwell Health Long Island, Jewish Medical Center, New York, United StatesNorthwell Health Long Island, Jewish Medical Center, New York, United StatesCold Spring Harbor Laboratory, Cold Spring Harbor, United States; Cancer Research UK – Cambridge Institute, University of Cambridge, Cambridge, United KingdomCold Spring Harbor Laboratory, Cold Spring Harbor, United States; Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, United StatesDespite 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.https://elifesciences.org/articles/66109lung cancerepigeneticserlotinib-resistantAXL |
| spellingShingle | Polona Safaric Tepes Debjani Pal Trine Lindsted Ingrid Ibarra Amaia Lujambio Vilma Jimenez Sabinina Serif Senturk Madison Miller Navya Korimerla Jiahao Huang Lawrence Glassman Paul Lee David Zeltsman Kevin Hyman Michael Esposito Gregory J Hannon Raffaella Sordella An epigenetic switch regulates the ontogeny of AXL-positive/EGFR-TKi-resistant cells by modulating miR-335 expression eLife lung cancer epigenetics erlotinib-resistant AXL |
| title | An epigenetic switch regulates the ontogeny of AXL-positive/EGFR-TKi-resistant cells by modulating miR-335 expression |
| title_full | An epigenetic switch regulates the ontogeny of AXL-positive/EGFR-TKi-resistant cells by modulating miR-335 expression |
| title_fullStr | An epigenetic switch regulates the ontogeny of AXL-positive/EGFR-TKi-resistant cells by modulating miR-335 expression |
| title_full_unstemmed | An epigenetic switch regulates the ontogeny of AXL-positive/EGFR-TKi-resistant cells by modulating miR-335 expression |
| title_short | An epigenetic switch regulates the ontogeny of AXL-positive/EGFR-TKi-resistant cells by modulating miR-335 expression |
| title_sort | epigenetic switch regulates the ontogeny of axl positive egfr tki resistant cells by modulating mir 335 expression |
| topic | lung cancer epigenetics erlotinib-resistant AXL |
| url | https://elifesciences.org/articles/66109 |
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