Abstract 1150: Targeting MET Exon 14 mutations with the selective small molecule inhibitor Savolitinib

Alterations in the MET oncogene occurs across a broad range of tumor indications. Amplification or mutations in MET lead to increased activity of downstream pathways including PI3K and MAPK, eventually resulting in tumor formation. Several small molecule inhibitors are currently in clinical trials, including the selective inhibitor Savolitinib(HMP-504, Volitinib, AZD6094), which shows single digit nanomolar activity in MET-amplified cell lines. Newly emerging data suggest mutations in MET causing complete skipping of Exon14 occur in approximately 4% of non-small cell lung cancer (NSCLC), and are more rare in other indications [1, 2]. MET exon14 skipping mutations were shown to be mutually exclusive from EGFRm, ALK and KRAS and can occur in the context of MET gene amplification [3]. Exon14 harbors the CBL binding site (Y1003), which is critical for receptor degradation after binding of its ligand, HGF, and suppression of downstream signaling events. Clinical trial results with less potent, pan RTK inhibitors Crizotinib(31nM GI50 vs 3nM for Savolitinib) and Cabozantinibshow promising early results, but fall short in long term responses. Therefore, better therapies targeting MET are needed. Human cell linemodels with Exon14 deletions are rare. Therefore, we used engineered cell lines to test the effect of Savolitinibon these mutations. To do this, we expressed MET-Y1003F mutants in NIH-3T3 and HEK293T cells. We found that Savolitinibpotently inhibited phospho-MET in both models expressing this mutant (100% phospho-MET inhibition). In addition, we tested whether or not Savolitinibcould inhibit HGF-dependent signaling and growth of a NSCLC cell line, NCI-H596. In the presence of FBS (10%), Savolitinibhad no effect on the growth rate of these cells, however was highly efficient at blocking HGF-dependent growth in the absence of FBS. To test the effect of this mutation in the background of amplification, we also tested the gastric cancer cell line Hs746T, which harbors exon14 skipping in addition to MET amplification. Savolitinibwas highly efficacious at blocking the growth of this cell line. Future studies are aimed at looking at the in vivo effect of Savolitinibtargeting exon14 mutants. These data provide a platform of evidence for using Savolitinibto target exon14 mutant MET in patients. 1. Paik, P.K., et al., Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon14 skipping. Cancer Discov, 2015. 5(8): p. 842-9. 2. Frampton, G.M., et al., Activation of MET via diverse exon14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov, 2015. 5(8): p. 850-9. 3. Cancer Genome Atlas Research, N., Comprehensive molecular profiling of lung adenocarcinoma. Nature, 2014. 511(7511): p. 543-50. Citation Format: Evan Barry, Elizabeth Maloney, Ryan Henry, Alexandra Borodovsky, Edwin Clark, MelanieFrigault, Michael Zinda, Celina D’Cruz. Targeting MET Exon14 mutations with the selective small molecule inhibitor Savolitinib. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1150.