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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
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    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.

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