Abstract

Abstract The fusion kinases of ROS1 and ALK have been identified as oncogene drivers in small portions of many malignancies, especially in non-small cell lung cancer (NSCLC). ALK/ROS1/MET inhibitor crizotinib has been approved by the US Food and Drug Administration for the treatment of ALK or ROS1-positive non-small cell lung cancer in 2011 and 2016, respectively. The emergence of drug resistance presents a major issue for targeted therapy. Although ceritinib, alectinib, and brigatinib have been approved for crizotinib-refractory ALK+ patients with NSCLC, treatment options for patients with ROS1+ NSCLC are limited, especially for crizotinib-refractory patients. Ceritinib and entectinib demonstrated clinical efficacy only in crizotinib-naïve ROS1+ patients. The most common resistance mechanisms to crizotinib treatment in ROS1+ NSCLC is the solvent front mutation ROS1 G2032R and gatekeeper mutation ROS1 L2026M. TPX-0005, a novel three-dimensional macrocycle with a much smaller size than current ROS1 inhibitors in the clinic, was designed to overcome clinical resistance mutations systematically. TPX-0005 potently inhibited both wild type and mutant ROS1s including solvent front mutations and gatekeeper mutations. TPX-0005 showed pico-molar activity against ROS1 kinase (IC50 0.076 nM) in Reaction Biology kinase assay. The comparison of TPX-0005 with other ROS1 inhibitors in Ba/F3 cell proliferation assays is presented in the table. In the xenograft tumor model studies, TPX-0005 dramatically caused tumor regression in the tumors carrying WT or solvent-front mutated ROS1 fusion gene. Overall, TPX-0005 demonstrated desired drug-like properties, good safety profile, and is a supreme ROS1 inhibitor against WT and various mutated ROS1s. A phase 1/2 clinical trial of TPX-0005 is actively being pursued (NCT03093116). CD74-ROS1 Ba/F3 Cell Proliferation Assay IC50 (nM)InhibitorWTG2032RD2033NL2026MS1986FS1986YTPX-0005<0.28.40.210<0.2<0.2Crizotinib9.71402139606.420.919Lorlatinib0.5262.42.4ND0.30.3Entrectinib25.42404ND2026NDNDCeritinib131.92000NDND14.226.9Brigatinib28.61385167.1211527.724.6Cabozantinib1.060.70.129.1NDND ND: not determined. Citation Format: J. Jean Cui, Dayong Zhai, Wei Deng, Evan Rogers, Zhongdong Huang, Jeffrey Whitten, John Lim, Yishan Li. TPX-0005, a supreme ROS1 inhibitor, overcomes crizotinib-resistant ROS1 mutations including solvent front mutation G2032R and gatekeeper mutation L2026M [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B185.

Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call