Abstract 7198: Preclinical efficacy of the combination of MEK inhibitor plus KRAS G12D inhibitor for non-small cell lung cancer with <i>KRAS G12D</i>

Abstract KRAS G12D is observed in 3 - 8% of non-small cell lung cancer (NSCLC). Currently, no targeted therapies are approved for solid tumors including NSCLC with KRAS G12D. MRTX1133 is a selective KRAS G12D inhibitor in advanced development. A previous preclinical data showed that MRTX1133 was effective in pancreatic carcinoma, but might not in NSCLC. Thus, we evaluated the efficacy of MRTX1133 monotherapy and investigated potential therapeutic strategies for NSCLC with KRAS G12D using in vitro and in vivo models. Cell viability assays demonstrated that MRTX1133 was less effective in KRAS G12D-mutated NSCLC cell lines. MRTX1133 suppressed phosphorylation of ERK in KRAS G12D-mutated NSCLC cell lines at 2 - 4 hours, but rebound of phosphorylation of ERK was observed at 24 - 48 hours. To identify potential combination drugs that can enhance the efficacy of MRTX1133, we evaluated phosphorylation of receptor tyrosine kinases in KRAS G12D-mutated NSCLC cell lines treated with MRTX1133 monotherapy and performed a drug combination screening for KRAS G12D-mutated NSCLC cell lines. Although no phosphorylation of receptor tyrosine kinases that could be combination drug candidates were observed, several MEK inhibitors, such as trametinib, selumetinib and binmetinib, enhanced the efficacy of MRTX1133 in cell viability assays. MEK inhibitors suppressed rebound of phosphorylation of ERK by MRTX1133 monotherapy at 24 - 48 hours. The combination of trametinib with MRTX1133 suppressed tumor growth compared to MRTX1133 monotherapy with tolerable toxicity in KRAS G12D-mutated NSCLC in vivo models. In conclusion, our findings indicate that the preclinical efficacy of MRTX1133 monotherapy was limited for NSCLC with KRAS G12D, and therapeutic potential of MEK inhibitors in combination with MRTX1133. Citation Format: Yu Tanaka, Mirai Tsukuda, Gaku Yamamoto, Eri Sugiyama, Hiroki Izumi, Tetsuya Sakai, Shigeki Umemura, Yoshitaka Zenke, Shingo Matsumoto, Kiyotaka Yoh, Koichi Goto, Hibiki Udagawa. Preclinical efficacy of the combination of MEK inhibitor plus KRAS G12D inhibitor for non-small cell lung cancer with KRAS G12D [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 7198.