The RAF/MEK clamp VS-6766 shows strong anti-tumor activity across multiple MAPK pathway alterations, with a preferential effect on KRAS G12V

Background: KRAS is the most frequently mutated RAS/RAF family member (mutated in 15% of cancers), followed by BRAF (5%) and NRAS (3%). Several MEK inhibitors (MEKi) are approved for V600E cancers, G12C inhibitor sotorasib non-small cell lung cancer (NSCLC). However, there still a need agents targeting other mutations (mt), including G12 V which ∼7%, ∼9% ∼19% NSCLC, colorectal pancreatic respectively. VS-6766 unique RAF/MEK clamp that potently inhibits kinase activity induces dominant negative RAF-MEK complex preventing phosphorylation ARAF, CRAF. This mechanism allows to block signaling without compensatory re-activation appears limit efficacy MEKi. Material Methods: In vitro assays were performed evaluate anti-proliferative human tumor lines with MAPK pathway alterations RAS-less mouse embryonic fibroblasts (MEFs) stably transfected various variants. The anti-tumor was assessed genetically engineered models (GEMM) V/Trp53 KO G12C/Trp53 NSCLC. Results: showed strong potency across carrying KRAS, BRAF, CRAF, or NF1 alterations. Among mt lines, differed variant, greatest observed > G12D, consistent through CRAF/MEK/ERK G12D more PI3 K/AKT/mTOR. Similarly, MEFs different variants, best G12C, least wildtype. Accordingly, NSCLC GEMM model, previously shown be CRAF-dependent, monotherapy induced stronger regression than corresponding model. Strikingly, combination FAK inhibition conferred regressions 87% (27/31) 71% (36/51) all tumors models, Clinically, objective responses occurred mainly patients 4 out 7 responders bearing (Guo, 2020). treated defactinib, preference also confirmed 2/2 reduction 4/6 (Krebs, 2021). Conclusions: These data support ongoing registration-directed study evaluating ± defactinib (NCT04620330), as well clinical combinations (NCT05074810) adagrasib (NCT05375994) No conflict interest.