NTRK1 and ROS1 inhibitors in NSCLC

Purpose: Efforts to discover drugs that overcome resistance to targeted therapies in patients with rare oncogenic alterations, such as NTRK1- and ROS1-rearrangements, are complicated by the cost and protracted timeline of drug discovery. Experimental design: In an effort to identify inhibitors of NTRK1 and ROS1, which are aberrantly activated in some patients with non-small cell lung cancer (NSCLC), we created and screened a library of existing targeted drugs against Ba/F3 cells transformed with these oncogenes. Results: This screen identified the FDA-approved drug cabozantinib as a potent inhibitor of CD74-ROS1 transformed Ba/F3, including the crizotinib-resistant mutants G2032R and L2026M (IC50 = 9, 26, and 11 nM, respectively). Cabozantinib inhibited CD74-ROS1-transformed Ba/F3 cells more potently than brigatinib (wild-type/G2032R/L2026M IC50 = 30/170/200 nM, respectively), entrectinib (IC50 = 6/2,200 /3,500 nM), and PF-06463922 (IC50 = 1/270/2 nM). Cabozantinib inhibited ROS1 autophosphorylation and downstream ERK activation in transformed Ba/F3 cells and in patient-derived tumor cell lines. The IGF-1R inhibitor BMS-536924, potently inhibited CD74-NTRK1 transformed compared to parental Ba/F3 cells (IC50 = 19 nM vs. > 470 nM). A patient with metastatic ROS1-rearranged NSCLC with progression on crizotinib was treated with cabozantinib and experienced a partial response. Conclusions: While acquired resistance to targeted therapies is challenging, this study highlights that existing agents may be repurposed to overcome drug resistance, and identifies cabozantinib as a promising treatment of ROS1-rearranged NSCLC after progression on crizotinib.

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