Abstract
Abstract ROS1 fusion oncogene represent a novel molecular target in a small subset of non-small cell lung cancers (NSCLC).The ROS1 fusion oncogene, such as CD74-ROS1, leads to constitutive ROS1 activation with potent transforming activity. In the ongoing phase 1 clinical trial, the response rate of crizotinib, ALK/MET/ROS1 tyrosine kinase inhibitor (TKI), in the patients with NSCLC harboring ROS1 fusions was around 60%. However, despite crizotinib has shown remarkable initial responses, cancers eventually develop resistance to crizotinib. In a recent report of a clinical resistance to crizotinib, G2032R mutation in ROS1 kinase domain was identified, which is analogous to the G1202R mutation found in crizotinib-resistant ALK-rearranged lung cancers. To further identify the mechanism of resistance to crizotinib in ROS1 fusion positive NSCLC, we established a model of acquired resistance by ENU mutagenesis screening using CD74-ROS1 addicted Ba/F3 cell line models. As the results, we identified several novel crizotinib resistance mutations including G2032R mutation. To overcome the resistance, we performed the drug screening with small molecular inhibitors, and identified several inhibitors including Foretinib, cMET/VEGFR inhibitor, effectively inhibit the survival of CD74-ROS1 expressing cells. Furthermore, we also identified that some of those inhibitors can overcome the resistance caused by G2032R mutation. Thus, we have developed a comprehensive model of acquired resistance to crizotinib in ROS1 fusion harboring NSCLC and identified therapeutic strategies to overcome the resistance. Citation Format: Ryohei Katayama, Yuka Kobayashi, Sumie Koike, Naoya Fujita. Therapeutic strategies to overcome the crizotinib resistance in ROS1-rearranged lung cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3717. doi:10.1158/1538-7445.AM2014-3717
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