Abstract A37: Implication of targeting YAP1 in KRAS-mutant lung cancer cells

Lung cancer is the leading cause of cancer death worldwide, and it is estimated that 1.6 million deaths occur per year. Non-small cell lung cancer (NSCLC), mainly consisting of adenocarcinoma and squamous cell carcinoma, accounts for more than 80% of all new lung cancers with poor prognosis. Cytotoxic chemotherapy has improved the prognosis of NSCLC, and new advances in the discovery of oncogenic drivers and specific targeted therapies have brought significant improvement in the outcome of NSCLC patients. KRAS is one of the most frequently mutated oncogenes in human NSCLC. Despite intense efforts to develop drugs targeting the mutant KRAS, no effective therapeutic strategies have been successfully made in the clinical stage. In an attempt to interrogate the therapeutic candidate for the obstacle named KRAS, we performed small-molecule screening by assessing drug sensitivity from cell viability assay. We have previously described the identification of benzimidazole derivatives as selective cytotoxic agents for KRAS-mutant lung cancer cells. Here, we report another compound, verteporfin, a YAP1 inhibitor, showed a significant effect for reducing cell viability in KRAS-mutant lung cancer cells. Further validation assays using 16 cell lines (8 KRAS-mutant and 8 wild-type) strengthened the results of the primary screening. Recent studies have provided the relationship between YAP1 and KRAS for tumorigenesis in various cancers and urged us to explore the YAP1 inhibitor as an archer of this evil oncogene, KRAS. To determine the role of YAP1 in these cascades, we carried out the validation assay to compare the effect of verteporfin and the knockdown of YAP1 on cell viability in KRAS-mutant lung cancer cells. Whereas verteporfin showed the inhibitory effects in KRAS-mutant lung cancer cells in a dose-dependent manner, YAP1 knockdown did not show such inhibitory effect to that extent. The results of Western blotting and immunofluorescence suggested that the effects between verteporfin and YAP1 knockdown showed different manner. These facts led us to formulate the hypothesis that the activity of verteporfin is not only serving as a YAP1 inhibitor but other mechanisms are involved. Thus, we planned to examine the difference between the effects of verteporfin and YAP1 knockdown with RNA sequencing analyses and evaluated the factors surrounding the Hippo pathway or other pathways. As a result, there are many genes that overlap between verteporfin treatment and YAP1 knoc