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

Activating KRAS mutations, including G12C and G12D, are detected in approximately 25% of human cancers. The most common KRAS mutation is G12C, which comprises nearly 15% of lung adenocarcinomas, 8% of colorectal carcinomas and 4% of pancreatic adenocarcinomas. AMG-510 from Amgen and MRTX849 from Mirati Therapeutics, both targeting the KRASG12C mutant, have shown encouraging results in clinical trials, showing a better overall response rate (ORR) and disease control rate (DCR) in KRAS G12C 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 next generation KRAS-G12C inhibitors, we have established AMG510 resistant MIA PaCa-2 pancreatic adenocarcinoma CDX models and lung, colorectal carcinoma PDX models. These resistant models were derived from sensitive models carrying the KRAS G12C mutation by prolonged treatment of AMG510 after several in vivo 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 KRAS-G12C inhibitor induced resistant CDX/PDX models, which could be used as tools to evaluate new KRAS-G12C inhibitors, as well as combinatorial strategies with KRAS-G12C inhibitors.



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