Abstract
Lung cancer has become the most prevalent neoplasm throughout the world with 1,2 million deaths per year. Molecular genetic analyses have suggested that KRAS mutation is much more frequency in NSCLC. Significant challenges are to develop selective pharmacological inhibitors for RAS mutation to treat cancers driven. In our study, we used the combinatorial strategy to target oncogene addiction for RAS-mutant cells and the data showed that ABT199 and irinotecan leads to RAS-mutant lung cancer cell growth inhibition and enhanced apoptosis in vitro and in vivo. Furthermore, PI3K/AKT signaling was down-regulated by the combination in KRAS-mutant lung cancer cells. Importantly, the effects of ABT199 and irinotecan combination are synergistic on the RAS-mutant lung cancer cells. Therefore, the combination suggests a strong synergy in vivo and a potential avenue for therapeutic treatment of KRAS-mutant cancers which are otherwise difficult targeted by small molecules.