Abstract 3004: Establishment of KRAS G12C mutant patient-derived xenograft (PDX) models for pre-clinical evaluation of KRAS G12C targeted anticancer therapy

Abstract

Abstract KRAS is one of the most prevalent oncogenes in human cancers. The G12C mutation results in an amino acid substitution at position 12 in KRAS, from a glycine (G) to a cysteine (C), lead to accretion of GTP-bound activated state KRAS and activation of downstream signaling pathways. In non-small cell lung cancer (NSCLC), KRAS p.G12C is the most common mutation, comprising nearly half of all KRAS mutations. Recent breakthrough work led to the development of selective inhibitors targeting the KRAS G12C mutation, which have shown promise in early clinical trials. However, the therapeutic benefit of targeted therapies can be impaired by intrinsic or acquired resistance mechanisms, suggesting an urgent need of combinatorial strategies to overcome the resistance to drugs targeting KRAS G12C.Here we report on the establishment of a panel of KRAS G12C mutant PDX models, encompass non-small cell lung cancer, colorectal cancer and gastric cancer. The activity of AMG510, a selective KRAS G12C inhibitors in clinical trial, was characterized in these PDX models. Data showed that the validated KRAS G12C mutant models display a range of sensitivity to single treatment of AMG510. Given that in clinic only 50% of NSCLC patients with KRAS G12C mutation would benefit from KRAS G12C targeted inhibitors, in order to provide an insights for clinical therapeutic strategy, we investigated the combinatorial strategies in NSCLC PDX models: (1) AMG510 combined with Opdivo in KRAS G12C/CD274 amplification models in hPBMC humanized mice; (2) AMG510 combined with EGFR inhibitor in KRAS G12C/EGFR overexpression models. The possible mechanisms of combination effect were discussed. Altogether, the panel of KRAS G12C mutant PDX models are valuable for the pre-clinical evaluation of KRAS G12C targeted anti-cancer therapies. Citation Format: Wenting Shi, Xuzhen Tang, Jingying Zhang, Xinhong Kuang, Yan Zhang, Jingjing Wang, Qingyang Gu, Qunsheng Ji. Establishment of KRAS G12C mutant patient-derived xenograft (PDX) models for pre-clinical evaluation of KRAS G12C targeted anticancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3004.