TY - JOUR
T1 - Gilteritinib overcomes lorlatinib resistance in ALK-rearranged cancer
AU - Mizuta, Hayato
AU - Okada, Koutaroh
AU - Araki, Mitsugu
AU - Adachi, Jun
AU - Takemoto, Ai
AU - Kutkowska, Justyna
AU - Maruyama, Kohei
AU - Yanagitani, Noriko
AU - Oh-hara, Tomoko
AU - Watanabe, Kana
AU - Tamai, Keiichi
AU - Friboulet, Luc
AU - Katayama, Kazuhiro
AU - Ma, Biao
AU - Sasakura, Yoko
AU - Sagae, Yukari
AU - Kukimoto-Niino, Mutsuko
AU - Shirouzu, Mikako
AU - Takagi, Satoshi
AU - Simizu, Siro
AU - Nishio, Makoto
AU - Okuno, Yasushi
AU - Fujita, Naoya
AU - Katayama, Ryohei
N1 - Funding Information:
R.K. received research grants from Chugai, TAKEDA, Toppan Printing, Daiichi-Sankyo. N.F. received research grants from API corporation. The remaining authors declare no competing interests.
Funding Information:
This study was supported in part by MEXT/JSPS KAKENHI grant number 17H06327 (to N.F.), 19H03524 and 20K21554 (to R.K.), 18K06594 (to M.A.), the grant from the AMED grant number JP20cm0106203h0005 and JP20ck0106472h0002 (to R.K.), and the grant from Nippon Foundation (to N.F.), and Uehara Memorial Foundation (to R.K.). MEXT as “Program for Promoting Researches on the Supercomputer Fugaku (Application of Molecular Dynamics Simulation to Precision Medicine Using Big Data Integration System for Drug Discovery)” (to Y.O.), and FOCUS Establishing Supercomputing Center of Excellence (to Y.O.). This research used computational resources of the HPCI system provided by Information Technology Center, the University of Tokyo (Oakbridge-CX) through the HPCI System Research Project (Project ID: hp200129). J.K. received a scholarship from Polish National Agency for Academic Exchange.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-021-21396-w
DO - 10.1038/s41467-021-21396-w
M3 - Article
C2 - 33627640
AN - SCOPUS:85101566967
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1261
ER -
