Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, 135-8550, Japan.
Department of Medical Genome Science, Graduate School of Frontier Science, The University of Tokyo, Tokyo, 108-8639, Japan.
Nat Commun. 2019 Aug 9;10(1):3604. 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.
ROS1 基因重排约见于 1-2%的 NSCLC 患者和胆管癌、胶质母细胞瘤或结直肠癌等其他几种癌症中。克唑替尼，一种 ALK/ROS1/MET 抑制剂，对 ROS1 重排的肺癌非常有效，已在临床上应用。然而，克唑替尼耐药是一个新出现的问题，在对克唑替尼耐药的患者中已经确定了几种耐药机制，如继发性激酶结构域突变（例如，ROS1-G2032R）。在此，我们在 ROS1 或 NTRK 重排癌症的临床前模型中对新型选择性 ROS1/NTRK 抑制剂 DS-6051b 进行了表征。DS-6051b 可显著抑制野生型和 G2032R 突变的 ROS1 重排癌症或 NTRK 重排癌症的体外和体内生长。在此，我们报告 DS-6051b 在临床前模型中对 ROS1 或 NTRK 重排的癌症有效，包括对克唑替尼耐药的 ROS1 阳性癌症，特别是对克唑替尼、劳拉替尼和恩曲替尼（下一代 ROS1 抑制剂）高度耐药的 G2032R 突变。
