Nintedanib inhibits the VEGFR-ERK signaling pathway in human KRAS-mutated cancer cells

KRAS mutations are significant drivers in various cancers, and existing drug discovery efforts targeting these mutations have largely been unsuccessful, highlighting the need for more effective therapies. In this study, screening library, which contains 1374 chemical compounds, identified Nintedanib, a VEGFR inhibitor, as having a potent and selective antiproliferative effect against KRAS-mutant cells, surpassing other VEGFR inhibitors. Nintedanib effectively suppressed tumor growth in xenografted mice with KRAS mutations and was found to significantly inhibit phosphorylated VEGFR2 levels and its downstream signaling molecules pAKT and pERK in KRAS-mutant cells, suggesting that VEGFR2 inhibition impacts the oncogenic AKT/ERK pathway. Furthermore, in VEGFR2-knockout cells, KRAS-GTP activity was reduced by inhibiting the SOS1 protein, which led to decreased phosphorylation of ERK, AKT, and DRP1, inducing apoptosis. Notably, overexpression of KRASG12D augmented VEGFR2 expression, establishing a positive feedback loop between KRAS mutations and VEGFR2 signaling within the ERK pathway. Immunohistochemical analyses of pancreatic cancer tissues revealed high VEGFR2 expression in 83% (67/80) of samples, significantly exceeding levels observed in normal pancreatic tissues. These findings highlight VEGFR2 as a promising molecular target and propose a novel therapeutic avenue for KRAS-mutant cancers.