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KRAS G12C inhibitors (G12Ci), sotorasib and adagrasib, have demonstrated antitumor activity in patients with KRAS G12C mutant (mt) non-small cell lung cancer (NSCLC), and sotorasib has recently received FDA approval. It has been shown that simultaneous targeting of multiple nodes in the RAS/RAF/MEK/ERK (MAPK) pathway may be optimal for durable response. Furthermore, acquired mutations in the MAPK pathway occur clinically upon progression on adagrasib. Therefore, clinical combinations with G12Ci are needed. VS-6766 is a unique dual RAF/MEK inhibitor. In contrast to MEK-only inhibitors (MEKi), VS-6766 is a potent allosteric inhibitor of MEK kinase activity and induces a dominant negative RAF/MEK complex preventing phosphorylation of MEK by BRAF and CRAF. The combination of VS-6766 with the focal adhesion kinase (FAK) inhibitor defactinib with an intermittent schedule has shown clinical activity for patients with KRAS G12V and KRAS G12C mt NSCLC with a manageable safety profile relative to MEKi. Here, we tested whether combination of G12Ci with VS-6766 for vertical blockade of RAS, RAF and MEK might yield superior pathway blockade and antitumor efficacy. In 3D proliferation assays, VS-6766 was synergistic with both sotorasib and adagrasib in reducing viability of a panel of KRAS G12C mt cancer cell lines. Accordingly, VS-6766 effectively suppressed MAPK pathway signaling (pMEK, pERK) as a single agent, and the combination of VS-6766 + G12Ci showed improved depth and duration of MAPK pathway inhibition relative to G12Ci alone in KRAS G12C mt NSCLC models in vitro and in vivo. Reverse phase protein array (RPPA) analysis showed stronger inhibition of cell cycle/proliferation markers (e.g. aurora A/B, cyclin B1, pRb, pCDK1, pS6) with the combination than with VS-6766 or G12Ci alone. Additionally, the combination showed stronger activation of pro-apoptotic markers (e.g. cleaved caspase 7) and potential resistance markers (e.g. pFAK) than either agent alone. We are currently testing VS-6766 against a panel of cell lines expressing mutations identified in patients progressing on adagrasib. In KRAS G12C mt NSCLC models in vivo, VS-6766 combination augmented tumor growth inhibition by sotorasib, whereas trametinib combination was much less effective in augmenting sotorasib efficacy. In the H358 KRAS G12C mt NSCLC model, sotorasib monotherapy or sotorasib + trametinib failed to induce substantial tumor regression, whereas sotorasib + VS-6766 induced >25% tumor regression in 10/10 mice. Similarly, in the H2122 KRAS G12C mt NSCLC model, sotorasib + VS-6766 induced >20% tumor regression in 5/10 mice while sotorasib or sotorasib + trametinib were relatively ineffective. These results support the imminent clinical evaluation of VS-6766 in combination with a G12C inhibitor for treatment of KRAS G12C mt NSCLC in both G12Ci naïve patients and patients progressing on G12Ci treatment. Citation Format: Silvia Coma, Sanjib Chowdhury, Julien Dilly, Monica Musteanu, Mariano Barbacid, Andrew J. Aguirre, Jonathan A. Pachter. Dual RAF/MEK inhibitor VS-6766 enhances antitumor efficacy of KRAS G12C inhibitors through vertical inhibition of RAS, RAF and MEK [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 402. |
