Preclinical characterization and antitumor efficacy of DS-6051b, a novel, orally available small molecule tyrosine kinase inhibitor of ROS1 and NTRKs

• Published in: European journal of cancer (1990) 2016-12, Vol.69, p.S35-S36
• Main Authors: Kiga, M, Iwasaki, S, Togashi, N, Takeda, Y, Kagoshima, Y, Kanai, K, Kamai, Y, Tominaga, Y, Isoyama, T
• Format: Article
• Language: English
• Subjects: Anticancer properties; Antitumor activity; c-Met protein; Cells; Clinical trials; Enzyme inhibitors; Fusion; Fusion protein; Hematology, Oncology and Palliative Medicine; In vitro methods and tests; In vivo methods and tests; Inhibitors; Kinases; Lung cancer; Malignancy; Medical research; Mice; Molecular chains; Mutation; Non-small cell lung carcinoma; Studies; Therapeutic applications; Tumors; Tyrosine; Tyrosine kinase inhibitors; Xenografts; Xenotransplantation
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/S0959-8049(16)32687-9

Background: Gene rearrangements of ROS1 or NTRKs (NTRK1, NTRK2, NTRK3) have been reported in various cancers including non-small cell lung cancer. These cancers express activated fusion kinases that drive tumor malignancy. Therefore, ROS1 and NTRKs may be promising therapeutic targets. The MET/ALKI/ROS1 inhibitor crizotinib has shown responses in patients with ROS1 fusions, however, acquired resistance to crizotinib has been a concern and potential resistance mechanisms including ROS1 kinase mutations are implicated. DS-6051b is a novel, orally available, small molecule tyrosine kinase inhibitor of ROS1 and NTRKs, and is currently being investigated in phase I clinical trials. In this study, we examined in vitro and in vivo activities of DS-6051 b against ROSI and NTRK5, including ROS1 mutations to characterize the compound. Material and Methods: In vitro inhibitory activity against ROSI and NTRKs was tested in biochemical and cell-based assays. Antitumor efficacy was examined in a mouse subcutaneous xenograft model using cells expressing ROS1 or NTRK fusion gene. In addition, the activity against crizotinib-resistant ROS1 mutant was evaluated using Ba/F3 cells expressing ROS1 fusion with gatekeeper mutation (L2026M). Results: Potent in vitro activity of DS-6051 b was shown against ROS1, NTRK1, NTRK2, and NTRK3 kinases with lC5Os of 0.2 nM to 2.3 nM. When the compound was administered orally to xenografted mice, the growth of KM12 cells harboring TPM3-NTRK1 fusion and U-118MG cells harboring FIG-ROS1 fusion were significantly inhibited at 25mg/kg and above. In Ba/F3-ROS1 allograft mice, tumor regression with inhibition of phospho-ROS1 in the tumor was observed even against the tumor with a ROS1 gatekeeper mutation, in which crizotinib has no significant effect. Conclusions: These results indicated potent in vitro and in vivo activities of DS-6051b against ROS1 and NTRKs, suggesting the potential of the compound for the targeted therapy against cancers with ROS1 or NTRKs gene rearrangements. Moreover, the potential for the effectiveness against acquired ROS1 resistant tumors is also demonstrated. DS-6051b is currently being evaluated in phase I cOnical trials.