Abstract 4531: The effects of MRTX1133 on antitumor immunity in KRASG12D-mutant lung cancer

Background: There is no effective treatment for KRASG12D-mutant tumors. Immune checkpoint inhibitors (ICIs) have improved survival rates for lung cancer patients, but they are less effective in non-small cell lung cancer (NSCLC) with KRASG12D mutations. MRTX1133 is a selective inhibitor of KRASG12D undergoing early clinical trials. This study aimed to investigate the immune landscape of a KRASG12D-mutant lung cancer mouse model and evaluate whether MRTX1133 could induce antitumor immunity. We also assessed whether MRTX1133 has anti-proliferative effects and can promote antitumor immunity in human KRASG12D-mutant lung cancer cell lines. Methods: We generated conditional KRASG12D-mutant mice by crossing CCSP-rtTA/TetO-Cre and LSL-KRASG12D knock-in mice, inducing lung-specific tumors with doxycycline-containing food. MRTX1133 was administered intraperitoneally at 10 mg/kg once daily for 4, 8, or 12 days. After treatment, lungs and spleens were collected for flow cytometry analysis, and lung cells from the 4-day treatment group underwent RNA sequencing. Human KRASG12D-mutant lung cancer cell lines (A427 and SK-LU-1) were treated with MRTX1133 for RNA-Seq, differential gene expression analysis, and gene set enrichment analysis (GSEA). CCL20 protein levels were further validated by Western blotting and ELISA. Results: Longer doxycycline exposure increased regulatory T cell (Treg) infiltration in lung tumors. Additionally, immune checkpoint molecules (ICMs) such as PD-L1, PD-1, TIGIT, TIM-3, and LAG-3 were upregulated in CD4+ and CD8+ T cells. MRTX1133 treatment inhibited KRASG12D tumor progression, reduced Treg percentages, and decreased PD-1 expression in CD4+ and CD8+ T cells. It also increased tumor-specific CD8+ effector T cell infiltration in lung tumors, and interferon-gamma was enriched in MRTX1133-treated lung cells. In human KRASG12D-mutant lung cancer cells, MRTX1133 increased immune-related gene expression and decreased cell division-related genes in both cell lines. GSEA showed enrichment of interferon-gamma and interferon-alpha in MRTX1133-treated SK-LU-1 cells, while DMSO-treated cells showed enrichment of cell division genes. Elevated CCL20 levels were confirmed in the SK-LU-1 MRTX1133-treated group. Conclusion: KRASG12D-mutant lung tumors in mice exhibited T cell exhaustion. MRTX1133 showed therapeutic efficacy in the preclinical KRASG12D-mutant lung cancer model, possibly by enhancing antitumor immune responses along with oncogenic signaling inhibition. In human KRASG12D-mutant lung cancer cell lines, MRTX1133 reduced cell proliferation and increased antitumor cytokine expression, especially in SK-LU-1 cells. These findings may support the development of new immunotherapeutic strategies for patients with KRASG12D-mutant lung cancer. Citation Format: Kunihiro Shono, Satoshi Watanabe, Takaaki Masuda, Tomoya Wakabayashi, Ryo Yamazaki, Yumi Ando, Ryo Suzuki, Susumu Tanaka, Tomohiro Tanaka, Koichiro Nozaki, Yu Saida, Naohiro Yanagimura, Masashi Arita, Miyuki Sato, Riuko Ohashi, Kenjiro Shima, Yosuke Kimura, Nobumasa Aoki, Yasuyoshi Ohshima, Toshiyuki Koya, Toshiaki Kikuchi. The effects of MRTX1133 on antitumor immunity in KRASGD-mutant lung cancer [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 4531.