AACR 2024 Poster 1942

Developing KRAS G12C Inhibitor-Resistant Tumor Models for Efficacy Evaluation of Next-Generation Anticancer Therapies

Jun Zhou, Aaron Hua, Jian Feng, Ning Bao, Dan Zhang, Jessie (Jingjing) Wang, Marrit Putker, Ludovic Bourre

KRAS is one of the most frequent mutated oncogenes and has been recognized as undruggable for many years. AMG510, the first therapy to directly target KRAS, was approved by the FDA to treat non-small cell lung cancer (NSCLC) bearing KRAS G12C mutation. However, the emergence of resistance in patients remains a challenge and limits its clinical benefits.

A variety of secondary mutations in KRAS attributing to the resistance have been identified. This requires robust in vitro and in vivo preclinical models to validate potential therapeutics targeting these mutations. To meet this challenge, a panel of KRAS G12C inhibitor-resistant tumor models was generated to evaluate clinical strategies to overcome resistance to KRAS-targeted therapies.

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• Methods including the introduction of a secondary KRAS mutation, including H95D, H95Q, H95R, Q61H and R68S, using CRISPR/Cas9
• Growth rate observed in selected clones compared to the parental line, cellular characterization of MIA PaCa-2-KRAS mutant cells in vitro
• CRISPR/Cas9 engineered second site KRAS mutations in cells harboring KRAS G12C mutation displayed a differentially resistant profile to KRAS G12C inhibitors

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