The new-generation selective ROS1/NTRK inhibitor DS-6051b overcomes crizotinib resistant ROS1-G2032R mutation in preclinical models

Ryohei Katayama (), Bo Gong, Noriko Togashi, Masaya Miyamoto, Masaki Kiga, Shiho Iwasaki, Yasuki Kamai, Yuichi Tominaga, Yasuyuki Takeda, Yoshiko Kagoshima, Yuki Shimizu, Yosuke Seto, Tomoko Oh-hara, Sumie Koike, Naoki Nakao, Hiroyuki Hanzawa, Kengo Watanabe, Satoshi Yoda, Noriko Yanagitani, Aaron N. Hata, Alice T. Shaw, Makoto Nishio, Naoya Fujita and Takeshi Isoyama ()
Additional contact information
Ryohei Katayama: Japanese Foundation for Cancer Research
Bo Gong: Japanese Foundation for Cancer Research
Noriko Togashi: Daiichi Sankyo Co., Ltd
Masaya Miyamoto: Daiichi Sankyo Co., Ltd
Masaki Kiga: Daiichi Sankyo Co., Ltd
Shiho Iwasaki: Daiichi Sankyo Co., Ltd
Yasuki Kamai: Daiichi Sankyo Co., Ltd
Yuichi Tominaga: Daiichi Sankyo Co., Ltd
Yasuyuki Takeda: Daiichi Sankyo Co., Ltd
Yoshiko Kagoshima: Daiichi Sankyo Co., Ltd
Yuki Shimizu: Japanese Foundation for Cancer Research
Yosuke Seto: Japanese Foundation for Cancer Research
Tomoko Oh-hara: Japanese Foundation for Cancer Research
Sumie Koike: Japanese Foundation for Cancer Research
Naoki Nakao: Daiichi Sankyo RD Novare Co., Ltd
Hiroyuki Hanzawa: Daiichi Sankyo RD Novare Co., Ltd
Kengo Watanabe: Daiichi Sankyo Co., Ltd
Satoshi Yoda: Massachusetts General Hospital Cancer Center
Noriko Yanagitani: Japanese Foundation for Cancer Research
Aaron N. Hata: Massachusetts General Hospital Cancer Center
Alice T. Shaw: Massachusetts General Hospital Cancer Center
Makoto Nishio: Japanese Foundation for Cancer Research
Naoya Fujita: Japanese Foundation for Cancer Research
Takeshi Isoyama: Daiichi Sankyo Co., Ltd

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract ROS1 gene rearrangement was observed in around 1–2 % of NSCLC patients and in several other cancers such as cholangiocarcinoma, glioblastoma, or colorectal cancer. Crizotinib, an ALK/ROS1/MET inhibitor, is highly effective against ROS1-rearranged lung cancer and is used in clinic. However, crizotinib resistance is an emerging issue, and several resistance mechanisms, such as secondary kinase-domain mutations (e.g., ROS1-G2032R) have been identified in crizotinib-refractory patients. Here we characterize a new selective ROS1/NTRK inhibitor, DS-6051b, in preclinical models of ROS1- or NTRK-rearranged cancers. DS-6051b induces dramatic growth inhibition of both wild type and G2032R mutant ROS1–rearranged cancers or NTRK-rearranged cancers in vitro and in vivo. Here we report that DS-6051b is effective in treating ROS1- or NTRK-rearranged cancer in preclinical models, including crizotinib-resistant ROS1 positive cancer with secondary kinase domain mutations especially G2032R mutation which is highly resistant to crizotinib as well as lorlatinib and entrectinib, next generation ROS1 inhibitors.

Date: 2019
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DOI: 10.1038/s41467-019-11496-z

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