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

Abstract
KRAS mutations are common in lung cancer patients and are associated with poor survival rates. Targeting the downstream pathways of KRAS has been explored as a potential strategy for treating KRAS-mutant tumors, but clinical results have shown limited success. In this study, we introduced a novel approach by combining RAF (AZ628) and STAT3 (BP-1-102) inhibitors. Our findings revealed that the combination of AZ628 and BP-1-102 produced a strong synergistic effect in KRAS(G12D) H838, KRAS(G12S) H292, and KRAS(G12V) H441 cells. This combination significantly enhanced inhibition of cell proliferation in vitro and tumor growth in vivo, promoting apoptosis more effectively than either inhibitor alone. Mechanistically, the AZ628 and BP-1-102 combination strongly suppressed MEK/ERK signaling pathway activation in KRAS-mutant lung cancer cells, suggesting that this combined treatment could be an effective therapy for lung cancers with KRAS mutations. Overall, AZ 628 our results support the targeting of oncogene addiction as a therapeutic strategy for lung cancer cells harboring KRAS mutations.