ENA 2022 Poster 122

Establishment of RET Inhibitor-Induced Resistant Patient-Derived Colorectal Cancer Xenograft Models

Aaron L. Hua, Leilei Chen, Jinyu Huang, Xiaobo Chen, Guo Sheng, Jessie J.J. Wang

Rearranged during transfection (RET), a transmembrane receptor tyrosine kinase, is involved in multi-system tissue development which includes nervous, hematopoietic, and gastrointestinal systems. Activating RET alteration, induced by gene fusions or point mutations, has been discovered in several different solid tumor types including thyroid cancer, non-small cell lung cancer (NSCLC), breast cancer, and colorectal cancer.

Recently, two RET-specific tyrosine kinase inhibitors (TKIs), selpercatinib (LOXO-292) and pralsetinib (BLU-667), were approved by the FDA for the treatment of thyroid cancer and NSCLC. Despite the encouraging efficacy of these RET inhibitors, acquired resistance, such as solvent-front RET G810R/S/C mutations has limited their clinical benefits. Therefore, to better investigate novel therapeutic strategies which can overcome the acquired resistance, we established patient-derived xenograft (PDX) colorectal cancer models with drug-induced resistance

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• Methods for establishment of colorectal cancer PDX resistant to RET-inhibitor
  
  
• Acquired gene mutations in tumor regrowth during pronlonged LOXO-292 treatment
  
  
• Response of PDX with different acquired RET mutations to LOXO-292

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