Abstract PR013: Targeting <i>KRAS</i> mutation to overcome immunotherapy resistance in <i>ARID1A</i>-mutated ovarian cancer

Abstract Introduction: ARID1A is a subunit of the SWI/SNF chromatin-remodeling complex and acts as a tumor suppressor. Inactivating mutations in ARID1A are common in ovarian clear cell carcinomas (OCCC; &amp;gt;50%) and ovarian endometrioid carcinomas (OEC; &amp;gt;30%) and these mutations are associated with more aggressive disease. However, effective treatments for ARID1A-mutated ovarian cancers are still lacking. While there is evidence that SWI/SNF complex inactivation sensitizes tumors to immune checkpoint blockers (ICBs), inconsistent results in clinical studies have limited the use of the ARID1A mutation as a biomarker for predicting ICB response in ovarian cancer. The purpose of this study is to identify biomarkers that predict ICB response in ARID1A-mutated ovarian cancers and to develop novel therapeutic strategies for overcoming ICB resistance in these tumors. Methods: We analyzed the data from a recent clinical trial conducted at MD Anderson Cancer Center evaluating a combination of anti-PD-L1 and anti-CTLA-4 in OCCCs. To explore genetic alterations that modify the response to the ICBs in ARID1A-mutated OCCCs, we performed an unbiased bioinformatic analysis of genetic alterations in this patient cohort. For preclinical studies, we utilized isogenic OCCC cell lines derived from a genetically engineered Arid1a -/- ; Pik3ca H1045R/+ mouse model and introduced KRAS hotspot mutations such as KRAS G12D . Immunocompetent syngeneic orthotopic OCCC models established using these isogenic cell lines were used to assess tumor suppressive effects in vivo. Mutant KRAS was inhibited by both RAS(ON) inhibitors including RMC-6236 as well as mutation-specific small molecules such as MRTX1133. Mechanistic studies included single-cell RNA sequencing and CD8+ T cell depletion in vivo. Results: The clinical trial showed significantly prolonged overall survival in OCCC patients with tumors harboring ARID1A mutation compared to those with ARID1A wild-type tumors. However, our unbiased analysis revealed that patients with concurrent ARID1A and KRAS mutations, which account for ∼20% of cases, had significantly shorter overall survival. In preclinical models, syngeneic orthotopic OCCC mouse tumors formed by Arid1a -/- ; Pik3ca H1045R/+ cells were highly responsive to the combination of anti-PD-1 and anti-CTLA-4 antibodies. In contrast, KRAS G12D mutant rendered the syngeneic orthotopic OCCC mouse tumors formed by Kras G12D/+ ; Arid1a -/- ; Pik3ca H1045R/+ cells not responsive to ICBs. Importantly, RAS(ON) inhibitor RMC-6236 reversed the ICB resistance in syngeneic mouse models. Similar effects were also observed using MRTX1133. Mechanistically, single cell analysis in vitro and loss of function studies in vivo show that this is CD8 effector T cell dependent. Conclusions: Our studies demonstrate that KRAS mutation is a biomarker that negatively predicts responses to ICBs in ARID1A-mutated ovarian cancers. Combination of clinical applicable KRAS inhibitors and ICBs is an effective therapeutic strategy for ARID1A/KRAS-mutated ovarian cancers. Citation Format: Ayumu Matsuoka, Mitsutake Yano, Xue Hao, Yuan Qi, Hao Nie, Rafal J. Zielinski, Yiming Fang, Xiaojin Luan, Rugang Zhang. Targeting KRAS mutation to overcome immunotherapy resistance in ARID1A-mutated ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr PR013.