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Gilteritinib overcomes lorlatinib resistance in ALK-rearranged cancer

Author

Listed:
  • Hayato Mizuta

    (Japanese Foundation for Cancer Research
    Keio University)

  • Koutaroh Okada

    (Japanese Foundation for Cancer Research
    The University of Tokyo)

  • Mitsugu Araki

    (Kyoto University)

  • Jun Adachi

    (National Institutes of Biomedical Innovation, Health and Nutrition)

  • Ai Takemoto

    (Japanese Foundation for Cancer Research)

  • Justyna Kutkowska

    (Japanese Foundation for Cancer Research)

  • Kohei Maruyama

    (Japanese Foundation for Cancer Research
    The University of Tokyo)

  • Noriko Yanagitani

    (Japanese Foundation for Cancer Research)

  • Tomoko Oh-hara

    (Japanese Foundation for Cancer Research)

  • Kana Watanabe

    (Miyagi Cancer Center)

  • Keiichi Tamai

    (Miyagi Cancer Center Research Institute)

  • Luc Friboulet

    (Université Paris Saclay)

  • Kazuhiro Katayama

    (Nihon University)

  • Biao Ma

    (Foundation for Biomedical Research and Innovation at Kobe (FBRI))

  • Yoko Sasakura

    (Foundation for Biomedical Research and Innovation at Kobe (FBRI))

  • Yukari Sagae

    (Kyoto University)

  • Mutsuko Kukimoto-Niino

    (RIKEN Center for Biosystems Dynamics Research)

  • Mikako Shirouzu

    (RIKEN Center for Biosystems Dynamics Research)

  • Satoshi Takagi

    (Japanese Foundation for Cancer Research)

  • Siro Simizu

    (Keio University)

  • Makoto Nishio

    (Japanese Foundation for Cancer Research)

  • Yasushi Okuno

    (Kyoto University)

  • Naoya Fujita

    (Japanese Foundation for Cancer Research)

  • Ryohei Katayama

    (Japanese Foundation for Cancer Research
    The University of Tokyo)

Abstract

ALK gene rearrangement was observed in 3%–5% of non-small cell lung cancer patients, and multiple ALK-tyrosine kinase inhibitors (TKIs) have been sequentially used. Multiple ALK-TKI resistance mutations have been identified from the patients, and several compound mutations, such as I1171N + F1174I or I1171N + L1198H are resistant to all the approved ALK-TKIs. In this study, we found that gilteritinib has an inhibitory effect on ALK-TKI–resistant single mutants and I1171N compound mutants in vitro and in vivo. Surprisingly, EML4-ALK I1171N + F1174I compound mutant-expressing tumors were not completely shrunk but regrew within a short period of time after alectinib or lorlatinib treatment. However, the relapsed tumor was markedly shrunk after switching to the gilteritinib in vivo model. In addition, gilteritinib was effective against NTRK-rearranged cancers including entrectinib-resistant NTRK1 G667C-mutant and ROS1 fusion-positive cancer.

Suggested Citation

  • Hayato Mizuta & Koutaroh Okada & Mitsugu Araki & Jun Adachi & Ai Takemoto & Justyna Kutkowska & Kohei Maruyama & Noriko Yanagitani & Tomoko Oh-hara & Kana Watanabe & Keiichi Tamai & Luc Friboulet & Ka, 2021. "Gilteritinib overcomes lorlatinib resistance in ALK-rearranged cancer," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21396-w
    DOI: 10.1038/s41467-021-21396-w
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