STAT3 inhibitor sensitized KRAS-mutant lung cancers to RAF inhibitor by activating MEK/ERK signaling pathway

KRAS is frequently mutated in patients with lung cancers, resulting in low survival rates. Inhibiting the downstream pathways of KRAS seems to be a feasible strategy to target KRAS-mutant tumors. However, the clinical outcomes only show limited success. Here, we developed a novel strategy by combining RAF (AZ628) and STAT3 (BP-1-102) inhibitors. The results showed that the AZ628 and BP-1-102 combination showed strongly synergistic effects on KRAS(G12D) H838, KRAS(G12S) H292 and KRAS(G12V) H441 cells and significantly enhanced the inhibition of cell proliferation in vitro and tumor growth in vivo by promoting apoptosis compared with one inhibitor alone. For mechanism, AZ628 and BP-1-102 combination markedly abrogated MEK/ERK signaling pathway activation in KRAS-mutant lung cancer cells suggesting the combination of RAF and STAT3 inhibitors is an effective therapy for treating lung cancer cells harboring KRAS mutations. Taken together, the current results indicate that oncogene addiction can be targeted for therapy in lung cancer cells harboring RAS-mutant.