AACR 2023 Poster 401

Developing KRAS G12C Inhibitor-resistant Tumor Models for Efficacy Evaluation of Next-generation Anticancer Therapies

Jun Zhou, Zi Ye, Ning Bao, Dan Zhang, Aaron Hua, Chenpan Nie, Jessie (Jingjing) Wang, Rajendra Kumari，Leo Price, Xiaoxi Xu

Several studies show that diverse genomic and histologic mechanisms can confer resistance to covalent KRAS G12C inhibitors, including KRAS mutation (3-5).  In this poseter, we generated a panel of KRAS G12C inhibitor-resistant tumor models by introducing a secondary KRAS mutation on top of G12C for use as in vitro and in vivo tools to develop possible strategies to overcome such resistance.

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• How KRAS double-mutant cells generated via CRISPR/Cas9 show remarkable resistance to KRAS G12C inhibitors in vitro.
  
  
• How this can be used to assess preclinical in vitro/in vivo efficacy of novel KRAS-targeted therapeutics aimed to overcome resistance in the clinic. 
  
  
• A series of KRAS G12C inhibitor-resistant cell lines and patient-derived organoids to better facilitate efficacy testing of KRAS-targeted therapeutics.

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