| Literature DB >> 33627640 |
Hayato Mizuta1,2, Koutaroh Okada1,3, Mitsugu Araki4, Jun Adachi5, Ai Takemoto1, Justyna Kutkowska1, Kohei Maruyama1,3, Noriko Yanagitani6, Tomoko Oh-Hara1, Kana Watanabe7, Keiichi Tamai8, Luc Friboulet9, Kazuhiro Katayama10, Biao Ma11, Yoko Sasakura11, Yukari Sagae4, Mutsuko Kukimoto-Niino12, Mikako Shirouzu12, Satoshi Takagi1, Siro Simizu2, Makoto Nishio6, Yasushi Okuno4, Naoya Fujita1, Ryohei Katayama13,14.
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.Entities:
Year: 2021 PMID： 33627640 DOI： 10.1038/s41467-021-21396-w
Source DB: PubMed Journal: Nat Commun ISSN： 2041-1723 Impact factor: 14.919