Abstract 1263: Dual RAF/MEK inhibitor VS-6766 enhances antitumor efficacy of KRAS-G12C inhibitors through a vertical pathway inhibition strategy
Authors: Silvia Coma, Sanjib Chowdhury, Jonathan A. Pachter
Journal: Cancer Research (2021)

Abstract KRAS is one of the most frequently mutated oncogenes in cancer, stimulating tumor growth through activation of the RAS/RAF/MEK/ERK pathway. G12C inhibitors (G12Ci), sotorasib (AMG 510) and adagrasib (MTRX849), have demonstrated promising antitumor activity in patients with KRAS G12C mutant (mt) non-small cell lung cancer (NSCLC). Several recent studies have shown that simultaneous targeting of multiple nodes in the RAS/RAF/MEK/ERK pathway may be optimal for durable pathway inhibition and response. VS-6766 is a unique dual RAF/MEK inhibitor. In contrast to other MEK inhibitors, VS-6766 is a potent allosteric inhibitor of MEK kinase activity which promotes a dominant negative RAF/MEK complex preventing phosphorylation of MEK by wildtype BRAF, BRAF V600E mt and CRAF. This unique mechanism allows VS-6766 to block MEK signaling without the compensatory activation of MEK that appears to limit the efficacy of other inhibitors. Clinical studies are ongoing evaluating VS-6766 alone or in combination with the focal adhesion kinase (FAK) inhibitor defactinib for the treatment of various solid tumors. Here, we tested the hypothesis that vertical pharmacological blockade of RAS, RAF and MEK with G12Ci in combination with VS-6766 might yield superior pathway blockade and antitumor efficacy. In 3D proliferation assays in vitro, VS-6766 was synergistic with both sotorasib and adagrasib in reducing viability of a panel of KRAS G12C mt NSCLC and colorectal cancer cell lines. Accordingly, VS-6766 effectively suppressed RAS pathway signaling (pMEK, pERK, p-p90RSK) across KRAS G12C mt NSCLC cell lines as a single agent, and the combination of VS-6766 + G12Ci showed improved depth and duration of RAS pathway signaling relative to G12Ci alone. Similarly, in the H2122 KRAS G12C mt NSCLC xenograft model, VS-6766 combination with sotorasib showed improved inhibition of pMEK and pERK in tumors relative to sotorasib alone. In KRAS G12C mt NSCLC xenograft models in vivo, combination with VS-6766 (0.3 mg/kg QD) augmented tumor growth inhibition by sotorasib (30 mg/kg QD) in the H2122 KRAS G12C mt NSCLC model, whereas trametinib (0.3 mg/kg QD) was much less effective in augmenting sotorasib efficacy. Sotorasib monotherapy induced &amp;gt;20% tumor regression in 0/10 mice, whereas combination of VS-6766, trametinib or a FAK inhibitor with sotorasib induced &amp;gt;20% tumor regression in 5/10, 1/10 and 4/10 mice, respectively, following 10 days of treatment. Strikingly, triple combination of VS-6766, sotorasib and a FAK inhibitor conferred tumor reductions of ≥35% in 10/10 mice. Similarly, in the H358 KRAS G12C mt NSCLC model, triple combination of VS-6766, sotorasib and a FAK inhibitor induced &amp;gt;35% tumor regression in 10/10 mice following 21 days of treatment. These results support the clinical evaluation of VS-6766 ± defactinib in combination with a G12C inhibitor for treatment of KRAS G12C mt solid tumors. Citation Format: Silvia Coma, Sanjib Chowdhury, Jonathan A. Pachter. Dual RAF/MEK inhibitor VS-6766 enhances antitumor efficacy of KRAS-G12C inhibitors through a vertical pathway inhibition strategy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1263.