The intermediate-activity (L597V)BRAF mutant acts as an epistatic modifier of oncogenic RAS by enhancing signaling through the RAF/MEK/ERK pathway.

摘要: L597V BRAF mutations are acquired somatically in human cancer samples and frequently coincident with RAS mutations. Germline also found several autosomal dominant developmental conditions known as RASopathies, raising the important question of how same mutation can contribute to both pathologies. Using a conditional knock-in mouse model, we show that endogenous expression Braf leads approximately twofold elevated kinase activity weak activation Mek/Erk pathway. This is associated induction RASopathy hallmarks including cardiac abnormalities facial dysmorphia but not sufficient for tumor formation. We combined G12D Kras modified oncogenesis such fibroblast transformation lung development were more reminiscent driven by high-activity V600E mutant. levels comparable those double-mutant cells, gene signature was similar induced than Kras. However, unlike Braf, pathway mediated Craf ATP-competitive RAF inhibitors paradoxical Mek/ Erk activation. Our data underpins cancer, epistatically modifies transforming effects driver oncogenes.