Abstract 2959: Establishment of KRAS-G12C inhibitor induced resistant tumor models enable the development of new generation KRAS-G12C inhibitors and combinatorial strategies

The KRAS (Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) gene is one of the most popular oncogenes in the recent targeted therapy research. Activating KRAS mutations including G12C, G12D, etc are detected in around 25% of human cancers. The most common KRAS mutation is G12C, which comprises nearly 15% of lung adenocarcinoma, 8% of colorectal carcinoma and 4% of pancreatic adenocarcinoma. AMG-510 from Amgen and MRTX849 from Mirati Therapeutics both targeting KRASG12C mutant have shown encouraging activities in early clinical trials, especially shown a better overall response rate (ORR) and disease control rate (DCR) in KRASG12C mutant non-small cell lung cancer (NSCLC). However, acquired resistance to KRAS-G12C inhibitors will occur after prolonged treatment, which limits the effective evaluation in clinical trials. Various combinatorial strategies have been tried to overcome the resistance to KRAS-G12C inhibitors, including co-targeting vertical Ras signaling pathway and combining KRAS-G12C inhibitors with chemotherapeutics or immunotherapies. In order to facilitate the development of KRAS-G12C inhibitors, we have established an AMG510 resistant MIA PaCa-2 pancreatic adenocarcinoma CDX model and several colorectal carcinoma PDX models. These resistant models were derived from sensitive models carrying KRASG12C mutation, by prolonged treatment of AMG510 during several passages until a stable drug resistance phenotype occurred. To explore the resistant mechanisms, we performed Western blotting on downstream effectors ERK and found AMG510 produced less inhibition effect on ERK phosphorylation level in the resistant models. We are also developing more CDX and PDX models which are resistant to KRAS-G12C inhibitors. Therefore these models can be used to simulate acquired resistance to KRAS-G12C inhibitors after prolonged treatment in clinic, and provide a new tool to evaluate new generation of KRAS-G12C inhibitors as well as the combinatorial strategies with KRAS-G12C inhibitors. Citation Format: Gaoxiang Liu, Wenting Shi, Qingyang Gu, Qunsheng Ji. Establishment of KRAS-G12C inhibitor induced resistant tumor models enable the development of new generation KRAS-G12C inhibitors and combinatorial strategies [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 2959.