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- Title
Gilteritinib overcomes lorlatinib resistance in ALK-rearranged cancer.
- Authors
Mizuta, Hayato; Okada, Koutaroh; Araki, Mitsugu; Adachi, Jun; Takemoto, Ai; Kutkowska, Justyna; Maruyama, Kohei; Yanagitani, Noriko; Oh-hara, Tomoko; Watanabe, Kana; Tamai, Keiichi; Friboulet, Luc; Katayama, Kazuhiro; Ma, Biao; Sasakura, Yoko; Sagae, Yukari; Kukimoto-Niino, Mutsuko; Shirouzu, Mikako; Takagi, Satoshi; Simizu, Siro
- 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. Resistance to ALK inhibitors such as lorlatinib often arise due to on-target mutations. Here, the authors show the multi-kinase inhibitor gilteritinib is effective against different mutations that arise during lorlatinib in ALK fusion positive lung cancer to cause resistance.
- Subjects
NON-small-cell lung carcinoma; GENE rearrangement; KINASE inhibitors; LUNG cancer; ETIOLOGY of cancer
- Publication
Nature Communications, 2021, Vol 12, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-021-21396-w