AACR 2025 Poster 5524

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

Jian Feng, Dan Zhang, Aaron Hua, Chenpan Nie, Jessie (Jingjing) Wang, Ludovic Bourre, Jun Zhou, Peng Wang

For decades, KRAS was considered undruggable due to the lack of suitable binding sites. However, advancements in bioengineering and chemistry have enabled the approval of targeted therapies. Success was first seen with allele-specific targeting of KRASG12C in non-small cell lung cancer (NSCLC), leading to the approval of sotorasib (AMG510, Lumakras™) and MRTX849 (Adagrasib, Krazati™). Despite their clinical benefits, resistance emerged in some patients due to secondary KRAS mutations, which necessitates next-generation or combination therapy development. In this study, we outline the development of KRASG12C inhibitor-resistant models to evaluate next-generation therapies.

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• A panel of well-characterized cell lines harboring different KRAS secondary mutations
  
  
• How to leverage the panel to get deeper insights into drug resistance and evaluate new therapeutic strategies
  
  
• Matched in vitro and in vivo models for a seamless transition from lead optimization to preclinical studies

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