Abstract LB285: RASH3D19 mediates RAS pathway activation and adaptive resistance to KRAS targeting drugs in cancer

Abstract Activating mutations in KRAS are major oncogenic drivers in pancreatic, colorectal, and lung cancers. Although mutant KRAS inhibitors have demonstrated clinical activity, their efficacy is frequently limited by adaptive resistance driven by feedback reactivation of RAS signaling. In this study, we identified RASH3D19 as a previously unknown mediator of RAS pathway activation through positive feedback signaling and therapeutic resistance to KRAS inhibitor drugs in KRAS mutant cancer. We demonstrate that mutant KRAS induces miR-222 through NF-κB, leading to suppression of the transcription factor ETS1 and consequent downregulation of ETS1-dependent miR-301a. Loss of miR-301a derepresses its target, RASH3D19, resulting in elevated RASH3D19 expression in KRAS-mutant cancer cells. Mechanistically, RASH3D19 promotes EGFR dimerization and facilitates assembly of an EGFR-GRB2-SOS2-SHP2-GAB1 complex, thereby enhancing activation of MAPK and PI3K-AKT signaling pathways. Genetic deletion or silencing of RASH3D19 suppresses RAS activation, impairs anchorage-independent growth, and significantly reduces tumor growth in vitro and in vivo. Importantly, RASH3D19 loss abrogates feedback reactivation of RAS signaling following treatment with allele-specific KRAS and pan-RAS inhibitors, resulting in increased drug sensitivity in KRAS-mutant pancreatic ductal adenocarcinoma, colorectal cancer, and lung cancer cell lines, patient-derived organoids, and cancer cell line mouse xenograft models. Collectively, these findings establish RASH3D19 as a critical effector of RAS pathway signaling and a therapeutic target for enhancing the efficacy of both mutant KRAS and pan-RAS inhibitors in clinical trials. Citation Format: Warapen Treekitkarnmongkol, Hiroshi Katayama, Deivendran Sankaran, Mei-Chee Tai, Sanchita Rauth, Hanxiao Chen, Tristian Nguyen, Kieko Hara, Fredrik I. Thege, Moorthy P. Ponnusamy, Surinder K. Batra, Huamin Wang, Ignacio I. Wistuba, Thomas D. Schmittgen, John V. Heymach, Scott Kopetz, Tony Hu, Wantong Yao, Anirban Maitra, Subrata Sen. RASH3D19 mediates RAS pathway activation and adaptive resistance to KRAS targeting drugs in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB285.