Abstract 1677: ASPC-1-MRTX-1133R as a useful cell line model for KRAS-G12D inhibitor development

Abstract Introduction: KRAS mutations occur in nearly 30% of human cancers, the most frequent ones being G12C, G12D and G12V. The approval of AMG510 in 2021 broke the curse of KRAS’s non-druggability. AMG510 targets the KRAS-G12C mutation and achieves up to 90% disease control rate, but drug resistance quickly develops. KRAS-G12D, the most prevalent and oncogenic KRAS mutation, still lacks inhibitors. MRTX-1133, the first reported highly selective KRAS-G12D inhibitor, is currently in the preclinical phase. Similarly, drug resistance will inevitably develop to KRAS-G12D inhibitors. Methods: To explore the resistance mechanisms of KRAS-G12D mutation, our group used ASPC-1 cell line, which naturally expresses KRAS-G12D, to generate the ASPC-1-MRTX-1133R cell line using a dose-escalation method after treating cells with a mutagenic agent. Specifically, ASPC-1 cells were treated by MRTX-1133 with increasing dosage for 4 weeks, the remaining live cells were harvested and designated as ASPC-1-MRTX-1133R. Cell survival assay showed that IC50 of ASPC-1-MRTX-1133R is >2000nM, 100-fold more resistant than the parental ASPC-1 cell line (22nM). We identified the potential resistance mechanisms using whole exome sequencing (WES) and RNA-Seq. The resistance to MRTX-1133 of ASPC-1-MRTX-1133R cell line was highly stable after 20 cell passages. Conclusion: The ASPC-1-MRTX-1133R cell line can be a useful in vitro model in the development of KRAS-G12D inhibitors. Citation Format: Guoqian Wang, Yao Tang, Tingduo Lv, Jinying Ning, Feng Hao. ASPC-1-MRTX-1133R as a useful cell line model for KRAS-G12D inhibitor development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1677.