Gilteritinib overcomes lorlatinib resistance in ALK-rearranged cancer

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, Kazuhiro Katayama, Biao Ma, Yoko Sasakura, Yukari Sagae, Mutsuko Kukimoto-Niino, Mikako Shirouzu, Satoshi Takagi, Siro Simizu, Makoto Nishio, Yasushi Okuno, Naoya Fujita and Ryohei Katayama ()
Additional contact information
Hayato Mizuta: Japanese Foundation for Cancer Research
Koutaroh Okada: Japanese Foundation for Cancer Research
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
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

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-21396-w

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