Abstract 3644: Identification of existing targeted agents that inhibit NTRK and ROS1 in lung cancer

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA All patients with oncogenic driver mutations in non-small cell lung cancer (NSCLC) who are treated with a targeted agent will eventually develop resistance. In an effort to identify inhibitors of NTRK1 and ROS1, which are inappropriately activated in NSCLC, we created and screened a library of existing targeted drugs against BaF3 cells transformed with these oncogenes. This screen identified the FDA-approved drug cabozantinib as a potent inhibitor of CD74-ROS1 (IC50 = 9 nM), including the crizotinib-resistant mutants G2032R (IC50 = 26 nM) and L2026M (IC50 = 11 nM), with no inhibition of the parental BaF3 cells (IC50 > 10 μM). AP26113, a dual ALK/EGFR inhibitor undergoing phase I/II clinical trials, also potently inhibited CD74-ROS1 (IC50 = 4 nM), including the crizotinib-resistant mutants G2032R (IC50 = 206 nM) and L2026M (IC50 = 84 nM), with weak inhibition of the parental BaF3 cells (IC50 > 1 μM). Both cabozantinib and AP26113 inhibited ROS1 autophosphorylation and downstream ERK activation in CD74-ROS transformed BaF3 cells and in the ROS1-rearranged NSCLC cell line HCC78. The FGFR3 inhibitor dovitinib, which is in phase III clinical trials for renal cell carcinoma, potently inhibited NTRK1 compared to parental BaF3 cells (IC50 = 69 nM vs > 1 μM), and blocked NTRK1 autophosphorylation and ERK activation. While acquired resistance to targeted therapies is a major clinical problem, this study highlights other existing agents that may overcome resistance, and identifies several promising candidates for clinical trials. Citation Format: Curtis Chong, Dalia Ercan, Magda Bahcall, Marzia Capelletti, Nathanael Gray, Pasi Janne. Identification of existing targeted agents that inhibit NTRK and ROS1 in lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3644. doi:10.1158/1538-7445.AM2015-3644