IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v10y2019i1d10.1038_s41467-018-08074-0.html
   My bibliography  Save this article

AXL confers intrinsic resistance to osimertinib and advances the emergence of tolerant cells

Author

Listed:
  • Hirokazu Taniguchi

    (Kanazawa University
    Nagasaki University Graduate School of Biomedical Sciences)

  • Tadaaki Yamada

    (Kanazawa University
    Kyoto Prefectural University of Medicine)

  • Rong Wang

    (Kanazawa University)

  • Keiko Tanimura

    (Kyoto Prefectural University of Medicine)

  • Yuta Adachi

    (Kanazawa University)

  • Akihiro Nishiyama

    (Kanazawa University)

  • Azusa Tanimoto

    (Kanazawa University)

  • Shinji Takeuchi

    (Kanazawa University)

  • Luiz H. Araujo

    (Brazilian National Cancer Institute)

  • Mariana Boroni

    (Brazilian National Cancer Institute)

  • Akihiro Yoshimura

    (Kyoto Prefectural University of Medicine)

  • Shinsuke Shiotsu

    (Japanese Red Cross Kyoto Daiichi Hospital)

  • Isao Matsumoto

    (Kanazawa University)

  • Satoshi Watanabe

    (Niigata University Graduate School of Medical and Dental Sciences)

  • Toshiaki Kikuchi

    (Niigata University Graduate School of Medical and Dental Sciences)

  • Satoru Miura

    (Niigata Cancer Center Hospital)

  • Hiroshi Tanaka

    (Niigata Cancer Center Hospital)

  • Takeshi Kitazaki

    (Japanese Red Cross Nagasaki Genbaku Hospital)

  • Hiroyuki Yamaguchi

    (Nagasaki University Graduate School of Biomedical Sciences)

  • Hiroshi Mukae

    (Nagasaki University Graduate School of Biomedical Sciences)

  • Junji Uchino

    (Kyoto Prefectural University of Medicine)

  • Hisanori Uehara

    (Tokushima University Graduate School)

  • Koichi Takayama

    (Kyoto Prefectural University of Medicine)

  • Seiji Yano

    (Kanazawa University
    Kanazawa University, Kakuma)

Abstract

A novel EGFR-tyrosine kinase inhibitor (TKI), osimertinib, has marked efficacy in patients with EGFR-mutated lung cancer. However, some patients show intrinsic resistance and an insufficient response to osimertinib. This study showed that osimertinib stimulated AXL by inhibiting a negative feedback loop. Activated AXL was associated with EGFR and HER3 in maintaining cell survival and inducing the emergence of cells tolerant to osimertinib. AXL inhibition reduced the viability of EGFR-mutated lung cancer cells overexpressing AXL that were exposed to osimertinib. The addition of an AXL inhibitor during either the initial or tolerant phases reduced tumor size and delayed tumor re-growth compared to osimertinib alone. AXL was highly expressed in clinical specimens of EGFR-mutated lung cancers and its high expression was associated with a low response rate to EGFR-TKI. These results indicated pivotal roles for AXL and its inhibition in the intrinsic resistance to osimertinib and the emergence of osimertinib-tolerant cells.

Suggested Citation

  • Hirokazu Taniguchi & Tadaaki Yamada & Rong Wang & Keiko Tanimura & Yuta Adachi & Akihiro Nishiyama & Azusa Tanimoto & Shinji Takeuchi & Luiz H. Araujo & Mariana Boroni & Akihiro Yoshimura & Shinsuke S, 2019. "AXL confers intrinsic resistance to osimertinib and advances the emergence of tolerant cells," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-018-08074-0
    DOI: 10.1038/s41467-018-08074-0
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-018-08074-0
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-018-08074-0?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Sarah Figarol & Célia Delahaye & Rémi Gence & Aurélia Doussine & Juan Pablo Cerapio & Mathylda Brachais & Claudine Tardy & Nicolas Béry & Raghda Asslan & Jacques Colinge & Jean-Philippe Villemin & Ant, 2024. "Farnesyltransferase inhibition overcomes oncogene-addicted non-small cell lung cancer adaptive resistance to targeted therapies," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-018-08074-0. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.