Abstract 1888: Unveiling mechanisms of MRTX1133 resistance in PDAC models.

Abstract Recent years have witnessed significant advances in the development of therapeutics targeting KRAS G12D in cancer patients. However, the emergence of drug resistance remains a formidable clinical challenge, and the underlying mechanisms remain largely unknown. To investigate these mechanisms, we established resistant cell lines through stepwise escalation of MRTX1133, the first covalent inhibitor of KRAS G12D to enter clinical evaluation, in KRAS G12D-mutant modelsThese resistant cells maintain stable phenotypes to MRTX-1133 both in vitro and in vivo, and exhibited broad cross-resistance to other KRAS G12D inhibitors, such as RMC9805 and HRS-4642, with partial resistance observed toward the pan-RAS inhibitor RMC6236.Bioinformatic analysis of both resistant models revealed a spectrum of convergent adaptive mechanisms, including: (1) altered oncogenic signaling networks, (2) upregulation of cell cycle and drug efflux regulators, and (3) epithelial-mesenchymal transition (EMT). Interestingly, the MRTX1133-R-GP2D model acquired secondary KRAS mutations (specifically H95Q, Y96H, Y96N, and D92N), indicating on-target resistance. In a contrast, the MRTX1133-R-KPC model exhibited chromosome 5 amplifications encompassing key metabolic and detoxification genes (notably CYP51 and CYP3A), accompanied by tumor microenvironment (TME) reprogramming and immune evasion.Together, these findings reveal comprehensive mechanisms of resistance to KRAS G12D inhibition. The established resistant models serve as physiologically relevant platforms for biomarker discovery and the development of rational combination therapies. Using these models, functional studies demonstrated that targeting core vulnerabilities—including the cell cycle, DNA damage repair, compensatory signaling pathways, metabolic modulators may overcome resistance phenotype. Citation Format: Qin Li. Unveiling mechanisms of MRTX1133 resistance in PDAC models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1888.