Abstract A045: Development of Patient-Derived Xenograft (PDX) Model with Acquired Resistance to KRASG12C Inhibitors

Abstract Introduction The KRASG12C mutation is found in 14% of non-small cell lung cancer (NSCLC). MRTX849 (adagrasib) and AMG510 (sotoracib), FDA approved KRASG12C inhibitors, have shown promising results in NSCLC. Despite the encouraging efficacy, acquired resistance has limited their clinical benefits, which involves not only secondary KRAS mutations, such as Y96D mutation, but also bypass signaling pathway activation through amplifications of epidermal growth factor receptor (EGFR) or MET. Therefore, to investigate novel therapeutic strategies which can overcome the acquired resistance, we have established two PDX models from a patient with acquired resistance to AMG510 and MRTX849, and developed one induced KRASG12C inhibitor resistant PDX model. Methods LU22001 was established from patient tumors which progressed under AMG510 treatment. Then LU22002 was established from tumors of the same patient that progressed under combined treatment of MRTX849 and a SHP2 inhibitor, TNO155. The PDX models were implanted subcutaneously and treated with AMG510 (50 mg/kg, daily), MRTX849 (50 mg/kg, daily) and MRTX849 (50 mg/kg, daily) combined with TNO155 (10 mg/kg, twice a day). In parallel, LU11786 was implanted subcutaneously and treated with AMG510 at 50 mg/kg, daily. The fastest growing tumor of the treatment group was isolated and inoculated into naïve mice. Then AMG510 treatment was given until the tumors showing limited response to AMG510. The induced resistant model was treated with crizotinib at 50 mg/kg, daily. Gene changes of these PDX tumors were analyzed by Whole Exome Sequencing (WES). Results In LU22001, tumor volume had increased by at least 57% for all treatment groups at day 42, whereas in LU22002, tumor volume had increased by over 744% following treatment with either KRASG12C inhibitors at day 49 and 261% with combination treatment, indicating disease progression, which was consistent with clinical observation. Additionally, LU22002 tumors were more resistant to treatment and showed a 17-fold amplification of the EGFR gene compared to LU22001. To mimic acquired resistance in clinic, a drug induced resistant model was established. AMG510 significantly inhibited LU11786 tumor growth with TGI of 84% on day 28. Until the 4th round of drug induction, all tumors presented complete resistance (TGI=-32%) to AMG510 treatment. WES data showed MET amplification in resistant tumors with a fold change of 2.2. Crizotinib, a MET inhibitor, largely overcame the acquired resistance with tumor regression (TGI of 102%). Noticeably, all 6 mice treated with combined treatment of crizotinib and AMG510 showed complete tumor regression after 17 days of treatment. Conclusion We have successfully developed KRASG12C inhibitor resistant NSCLC PDX models derived from one patient with acquired resistance to AMG510 and MRTX849 treatments, and in vivo induced KRASG12C inhibitor resistant PDX model. EGFR or MET gene amplification was observed in these resistant models, which can be used to evaluate innovative combination strategies. Citation Format: Aaron Li. Hua, Jinxi Wang, Qingzhi Liu, Tina Zhang, Wubin Qian, Ludovic Ludovic, Jessie Jingjing. Wang. Development of Patient-Derived Xenograft (PDX) Model with Acquired Resistance to KRASG12C Inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A045.