Abstract 4332: Concomitant therapy leveraging antibody-pan-<i>KRAS</i>mt siRNA conjugate for PDAC and LUAD harboring <i>KRAS</i> mutations

Abstract Background: RAS is the most frequently mutated oncogene, with KRAS being the most mutated RAS isoform and accounting for 85% of RAS mutations observed in human cancers. KRAS mutation plays a crucial role in cancer initiation and progression and confers resistance to treatment. KRAS mutation is present in 90% of pancreatic ductal adenocarcinoma (PDAC) and 35% of lung adenocarcinoma (LUAD). With FDA’s approval of the first-in-class KRASG12C inhibitor LUMAKRAS® for the lung cancer in 2021, the emergence of secondary mutations continues to pose challenges in the clinical treatment of KRAS-mutant (KRASmt) cancers via inhibition of the single mutations. The goal of the current study was to investigate the impact of KRAS oncogene silencing by antibody-pan-KRASmt siRNA conjugates (AOCs) on the pancreatic and lung tumor growth. A series of pan-KRASmt siRNA sequences that target a wide range of KRAS mutations were selected and ligated to a tumor targeting antibody utilizing GeneQuantum’s (GQ) proprietary iGDCTM conjugation platform. The therapeutic potential of these AOCs with and without gemcitabine was examined in the cancer cell lines/patient derived organoid (PDO) models and subcutaneous CDX/PDX mouse models. Results: GQ’s iGDCTM conjugation process yielded unprecedented pure DAR1 pan-KRASmtAOCs, with over 98% purity confirmed by HPLC analysis. These candidate AOCs achieved potent target knockdown with reduced phosphorylation level of downstream effectors and significantly inhibited cell proliferation in multiple KRAS mutant cell lines/PDOs. The lead AOCs selected from the in vitro testing achieved enhanced tumor exposure compared to non-targeting isotype AOC in the CDX/PDX mice, and pharmacological reduction of oncogenic KRAS mutations suppressed the growth of tumor xenografts. Combined treatment of the lead pan-KRASmt AOC with gemcitabine demonstrated synergistic effects with prolonged survival rate and dramatically reduced mean tumor volume. Conclusion: GQ’s pan-KRASmt AOC demonstrated the benefit of the tumor enrichment and the positive impact on the tumor regression. The additive tumor reduction outcome via combining with gemcitabine suggested the potential sensitization effect of pan-KRASmt AOC on the conventional chemotherapy. Our findings in the present study unveiled a new path toward addressing KRAS-driven refractory cancers with tumor targeting siRNA therapy covering multiple KRAS mutations. Citation Format: Aiyun Wen, Jing Guo, Zengyan Mu, Chengang Zhou, Junhao Wang, Tongtong Hu, Haibo He, Meijun Xiong, Cong Liu, Paul H. Song, Gang Qin. Concomitant therapy leveraging antibody-pan-KRAS mt siRNA conjugate for PDAC and LUAD harboring KRAS mutations [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 4332.