Metformin combined with CB-839 specifically inhibits KRAS-mutant ovarian cancer

Abstract

KRAS mutations can cause metabolic reprogramming in ovarian cancer, leading to an increased metastatic capacity. This study investigated the metabolic reprogramming changes induced by KRAS mutations in ovarian cancer and the mechanism of action of metformin combined with a glutaminase 1 inhibitor (CB-839). KRAS-mutant ovarian cancer accounted for 14% of ovarian cancers. The expression of glucose metabolism-related (PFKFB3, HK2, GLUT1, and PDK2) and glutamine metabolism-related enzymes (GLS1 and ASCT2) was elevated in KRAS-mutant ovarian cancer cells compared with that in wild-type cells. KRAS-mutant cells had a higher aerobic oxidative capacity than did wild-type cells. Metformin inhibited proliferation, the expression of glucose metabolism-related enzymes, and the aerobic oxidative capacity of KRAS-mutant cells compared with those of control cells. Furthermore, it enhanced the expression of glutamine metabolism-related enzymes in KRAS-mutant cells. Metformin combined with CB-839 inhibited the proliferation and aerobic oxidation of KRAS-mutant cells to a greater extent than that observed in wild-type cells. Additionally, the inhibitory effects of metformin and CB-839 in the KRAS-mutant ovarian cancer NOD-SCID mouse model were significantly stronger than those in the drug-alone group. KRAS mutations lead to enhanced glucose and glutamine metabolism in ovarian cancer cells, which was inhibited by metformin combined with CB-839.