Abstract 5532: Combinational targeted therapy effects on EphA2 and KRAS G12C inhibitor against KRAS G12C mutated non-small cell lung cancer cells

Abstract Background: KRAS is the most frequent oncogene in non-small cell lung cancer (NSCLC), and some KRAS G12C inhibitors have been clinically developed for treatment of KRAS G12C-mutated NSCLC patients. However, these KRAS G12C inhibitors have shown limited efficacy, and developing novel treatment strategy is warranted to improve clinical prognosis in this clinical population. EphA2, a receptor tyrosine kinase overexpressed in various cancers including NSCLC, plays a critical role in tumorigenesis and cancer progression, with high expression levels associated with poor prognosis. Recent studies indicate that targeting EphA2 can effectively inhibit tumor growth and induce apoptosis in KRAS-mutated NSCLC, underscoring its potential as a promising therapeutic target. Methods: In this preclinical study, we investigated the combined effect and underlying mechanisms of KRAS G12C inhibitors and EphA2 inhibition using multiple human KRAS G12C-mutated lung cancer cell lines. Results: The combined inhibition of KRAS G12C and EphA2 resulted in enhanced suppression of cell proliferation via increasing cell apoptosis in a subset of these KRAS G12C-mutant lung cancer cells. The KRAS G12C and EphA2 inhibitor combination also suppressed cell migration, compared with the effects in each monotherapy. Cell line-derived xenograft model indicated that the combination of KRAS G12C inhibitor plus EphA2 inhibitor enhanced anti-tumor effects compared with KRAS G12C inhibitor monotherapy. Further examination of apoptosis-related proteins revealed that the combination treatment reduced Mcl-1 expression. Additionally, combining KRAS G12C with an Mcl-1 inhibition led to further increases in cell death and enhanced suppression of cell proliferation. Conclusions: The combination of KRAS G12C inhibitors and EPhA2 inhibition is expected as the promising strategy for those tumors. Citation Format: Hayato Kawachi, Tadaaki Yamada, Yuki Katayama, Takayama Koichi. Combinational targeted therapy effects on EphA2 and KRAS G12C inhibitor against KRAS G12C mutated non-small cell lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5532.