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

  1. Polona Safaric Tepes
  2. Debjani Pal
  3. Trine Lindsted
  4. Ingrid Ibarra
  5. Amaia Lujambio
  6. Vilma Jimenez Sabinina
  7. Serif Senturk
  8. Madison Miller
  9. Navya Korimerla
  10. Jiahao Huang
  11. Lawrence Glassman
  12. Paul Lee
  13. David Zeltsman
  14. Kevin Hyman
  15. Michael Esposito
  16. Greg Hannon
  17. Raffaella Sordella  Is a corresponding author
  1. Cold Spring Harbor Laboratory, United States
  2. Icahn School of Medicine at Mount Sinai, United States
  3. Northwell Health Long Island, United States
Research Article
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Cite this article as: eLife 2021;10:e66109 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.

Data availability

The data generated or analyzed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Polona Safaric Tepes

    Cancer Center, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Debjani Pal

    Cancer Center, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Trine Lindsted

    Cancer Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Ingrid Ibarra

    Cancer Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Amaia Lujambio

    Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2798-1481
  6. Vilma Jimenez Sabinina

    Cancer Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Serif Senturk

    Cancer Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Madison Miller

    Cancer Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Navya Korimerla

    Cancer Center, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Jiahao Huang

    Cancer Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Lawrence Glassman

    thoracic surgery, Northwell Health Long Island, New Hyde Park, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Paul Lee

    thoracic surgery, Northwell Health Long Island, New Hyde Park, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. David Zeltsman

    thoracic surgery, Northwell Health Long Island, New Hyde Park, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Kevin Hyman

    thoracic surgery, Northwell Health Long Island, New Hyde Park, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Michael Esposito

    thoracic surgery, Northwell Health Long Island, New Hyde Park, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Greg Hannon

    School of Biological Sciences, Cold Spring Harbor Laboratory, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Raffaella Sordella

    Cancer Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    For correspondence
    sordella@cshl.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9745-1227

Funding

No external funding was received for this work.

Ethics

Human subjects: The collection of human lung tissue samples and blood for this study was covered by Northwell Health/Cold Spring Harbor Laboratory IRB #TDP-TAP 1607 (Raffaella Sordella/10/11/16 ). The samples were acquired from patients already undergoing thoracic procedures (e.g. surgical tumor resection, biopsy) at Huntington Hospital. All study participants provided informed consent for the use of their lung tissue and blood for research purposes. Participants were informed of study aims, the potential risks and benefits of participation, and that any discoveries facilitated by the analysis of their tissues might be published. The participants were informed that their names would not be associated their samples in any publication or presentation of research findings.

Reviewing Editor

  1. Michael R Green, Howard Hughes Medical Institute, University of Massachusetts Medical School, United States

Publication history

  1. Received: December 29, 2020
  2. Accepted: June 10, 2021
  3. Accepted Manuscript published: July 13, 2021 (version 1)
  4. Version of Record published: July 16, 2021 (version 2)

Copyright

© 2021, Safaric Tepes et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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