AACR 2016: Activity of Savolitinib against MET Ex14 mutations and resistance to METi through decoupling from MYC expression
Abstract (please download the poster for full details)
Authors: Evan Barry, Ryan Henry, Alexandra Borodovsky, Elizabeth Maloney, Brendon Ladd, Melanie Frigault, Michael Zinda, Edwin Clark, Alwin Schuller and Celina D’Cruz
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 Exon 14 occur in approximately 4% of non-small cell lung cancer (NSCLC), and are more rare in other indications. Exon 14 harbors the CBL binding site (Y1003), which is critical for receptor degradation after binding of it’s ligand, HGF, and suppression of downstream signaling. Clinical trial results with less potent, pan RTK inhibitors Crizotinib (31nM GI50 vs 3nM for Savolitinib) and Cabozantinib show promising early results, but fall short in long term responses. Therefore, better therapies targeting MET are needed.
We utilized engineered, as well as endogenously expressing MET Ex14 mutant models to determine activity of Savolitinib. We found that Savolitinib potently inhibited phosho-MET in both model types. In addition, we found that savolitinib inhibited HGF-induced growth of the NSCLC model H596, which harbors loss of exon 14. In addition to the MET exon14 patient population, MET amplification also drives tumor formation in EGFR WT NSCLC. We previously presented EGFR activation as a resistance mechanism to Savolitinib in some clonal subpopulations. Here, we present an underlying mechanism of resistance found in all clones tested. We found that decoupling of MYC expression from MET activity was a hallmark of resistance. Overexpression of MYC in parental H1993 cells in a doxycycline-dependent manner resulted in resistance to Savolitinib. Parental as well as Savolitinib resistant H1993s depended on MYC expression, as knockdown resulted in loss of viability.
Together, this data demonstrates that Savolitinib is active against clinically relevant MET Ex14 mutations in addition to amplification, and that resistance ultimately may develop through decoupling MYC activity from MET signaling.