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 SimizuMakoto Nishio, Yasushi Okuno, Naoya Fujita, Ryohei Katayama

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article number1261
JournalNature communications
Issue number1
Publication statusPublished - 2021 Dec

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Fingerprint Dive into the research topics of 'Gilteritinib overcomes lorlatinib resistance in ALK-rearranged cancer'. Together they form a unique fingerprint.

Cite this