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

• Published in: Nature communications Vol. 10; no. 1; pp. 3604 - 12
• Main Authors: Katayama, Ryohei, Gong, Bo, Togashi, Noriko, Miyamoto, Masaya, Kiga, Masaki, Iwasaki, Shiho, Kamai, Yasuki, Tominaga, Yuichi, Takeda, Yasuyuki, Kagoshima, Yoshiko, Shimizu, Yuki, Seto, Yosuke, Oh-hara, Tomoko, Koike, Sumie, Nakao, Naoki, Hanzawa, Hiroyuki, Watanabe, Kengo, Yoda, Satoshi, Yanagitani, Noriko, Hata, Aaron N., Shaw, Alice T., Nishio, Makoto, Fujita, Naoya, Isoyama, Takeshi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.08.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 631/67/1612/1350; 64/60; 692/4028/67/1059/153; 692/4028/67/1059/2326; Benzamides - pharmacology; Cancer; Carcinoma, Non-Small-Cell Lung - genetics; Cell Line, Tumor; Cell Survival - drug effects; Cholangiocarcinoma; Colorectal carcinoma; Crizotinib - pharmacology; Drug Development; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Gene rearrangement; Glioblastoma; Humanities and Social Sciences; Humans; Indazoles - pharmacology; Inhibitors; Kinases; Lactams, Macrocyclic - pharmacology; Lung cancer; Lung Neoplasms - genetics; Membrane Glycoproteins - antagonists & inhibitors; multidisciplinary; Mutation; Mutation - drug effects; Non-small cell lung carcinoma; Protein Kinase Inhibitors - pharmacology; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - genetics; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - genetics; Receptor, trkB - antagonists & inhibitors; Science; Science (multidisciplinary); Targeted cancer therapy
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-11496-z

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. The treatment of ROS1-rearranged non-small cell lung cancer with the TKI crizotinib is limited due to the emergence of resistance. Here, the authors develop a new ROS1/NTRK inhibitor, DS-6051b, which overcomes crizotinib resistance in preclinical models.