Synergistic effects of FGFR1 and PLK1 inhibitors target a metabolic liability in KRAS-mutant cancer

ABSTRACT: KRAS oncoprotein is commonly mutated in human cancer but effective therapies specifically targeting KRAS-driven tumors remain elusive. Here we show that combined treatment with fibroblast growth factor receptor 1 (FGFR1) and polo-like kinase 1 (PLK1) inhibitors evoke synergistic cytotoxicity in KRAS-mutant tumor models in vitro and in vivo. Pharmacological and genetic suppression of FGFR1 and PLK1 synergizes to enhance anti-proliferative effects and cell death in KRAS-mutant lung and pancreatic but not colon nor KRAS-wild-type cancer cells. Mechanistically, co-targeting FGFR1 and PLK1 upregulate reactive oxygen species (ROS), leading to oxidative stress-activated c-Jun N-terminal kinase (JNK)/p38 pathway and E2F1-induced apoptosis. We further delineate that autophagy protects from PLK1/FGF

SUBMITTER: Prof. Ren-Wang Peng 

PROVIDER: S-SCDT-EMM-2020-13193 | biostudies-other |

REPOSITORIES: biostudies-other