ROS1 rearrangement was observed in about 1 % of NSCLC patients and in several other cancers such as cholangiocarcinoma, glioblastoma, or colorectal cancer. To date, crizotinib, an ALK/ROS1 inhibitor was approved and widely used for the treatment of ROS1 rearranged NSCLC. However, the tumor relapses within a few years due to the emergence of crizotinib resistance by the secondary mutations in ROS1 kinase domain (e.g. G2032R) or other unidentified mechanisms. In this study, we explored crizotinib resistance mechanisms using ENU mutagenesis screening and the analysis of crizotinib resistant patient’s pleural effusion. We found several secondary mutations in ROS1 kinase domain including previously reported mutations. From a crizotinib resistant patient’s specimen, no secondary mutation in ROS1 was observed. By establishing a cell line from the specimen, we performed kinase inhibitor screening combined with crizotinib, and found that a combination of crizotinib with dasatinib or a few other tyrosine kinase inhibitors can suppress the growth. These results suggested that a bypass pathway mediated resistance through Src family kinase conferred resistance in this crizotinib resistant case. For overcoming the secondary ROS1 mutations mediated crizotinib resistance, we characterized several ROS1 inhibitors including a new selective ROS1/NTRK inhibitor DS-6051b in preclinical models of ROS1-rarranged cancers by newly establishing cell lines from TKI naïve ROS1 fusion positive NSCLC patients, or developing resistant mutation harboring HCC78 (SCL34A2-ROS1) or Ba/F3-CD74-ROS1 cell line models. Using these preclinical models, we demonstrated that DS-6051b induced dramatic growth inhibition of both wild type and G2032R mutant ROS1–rearranged cancers in vitro and in vivo, suggesting that DS-6051b might be effective in treating wildtype and crizotinib resistant mutant ROS1-rearranged lung cancer. This study revealed that potential resistance mechanisms in ROS1-rearranged NSCLC are similar to those identified in ALK rearranged NSCLC, and next-generation ROS1 inhibitor provides future promising therapeutic strategies to overcome the secondary mutation mediated resistance.
Citation Format: Ryohei Katayama, Bo Gong, Makoto Nishio, Naoya Fujita. Crizotinib resistance mechanisms and potential therapeutic strategies to overcome the resistance in ROS1-rearranged non-small cell lung cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C084. doi:10.1158/1535-7163.TARG-19-C084