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Ref Type Journal Article
PMID (31399568)
Authors Katayama R, Gong B, Togashi N, Miyamoto M, Kiga M, Iwasaki S, Kamai Y, Tominaga Y, Takeda Y, Kagoshima Y, Shimizu Y, Seto Y, Oh-Hara T, Koike S, Nakao N, Hanzawa H, Watanabe K, Yoda S, Yanagitani N, Hata AN, Shaw AT, Nishio M, Fujita N, Isoyama T
Title The new-generation selective ROS1/NTRK inhibitor DS-6051b overcomes crizotinib resistant ROS1-G2032R mutation in preclinical models.
Journal Nature communications
Vol 10
Issue 1
Date 2019 08 09
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ETV6 - NTRK3 Advanced Solid Tumor sensitive DS6051b Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing ETV6-NTRK3 were sensitive to treatment with DS6051b in culture, demonstrating cell growth inhibition (PMID: 31399568). 31399568
EML4 - ALK Advanced Solid Tumor sensitive DS6051b Preclinical - Cell culture Actionable In a preclinical study, cells expressing EML4-ALK were sensitive to treatment with DS6051b in culture, demonstrating cell growth inhibition (PMID: 31399568). 31399568
ETV6 - NTRK2 Advanced Solid Tumor sensitive DS6051b Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing ETV6-NTRK2 were sensitive to treatment with DS6051b in culture, demonstrating cell growth inhibition (PMID: 31399568). 31399568
ETV6 - NTRK1 Advanced Solid Tumor sensitive DS6051b Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing ETV6-NTRK1 were sensitive to treatment with DS6051b in culture, demonstrating cell growth inhibition (PMID: 31399568). 31399568