BRAF V600E Expression in c-Kit+ Interstitial Cells of Cajal Drives Gastrointestinal Stromal Tumor Formation in Mice

Gastrointestinal stromal tumors (GIST) are rare sarcomas arising predominantly in the stomach and small intestine, with limited incidence in other gastrointestinal sites. GIST originates from c-KIT-/DOG1-positive interstitial cells of Cajal (ICC) most commonly driven by activating gain-of-function mutations in the c-KIT and PDGFRA genes. However, a subset of these malignancies, defined as wild-type GIST (WT-GIST), has mutations in the RAS pathway genes (e.g., NF1, KRAS, and BRAF), succinate dehydrogenase subunit genes, and rare gene fusions. A major obstacle in understanding WT-GIST pathogenesis and treatment resistance has been the lack of robust in vivo models. In this study, we report the development of a fully penetrant mouse model of BRAF-driven GIST by inducing BRAFV600E expression in c-Kit+ ICC. Unlike previous models which targeted only subsets of ICC leading to hyperplasia, the use of c-KitCreERT2 enables broader targeting, including ICC progenitors, resulting in rapid, multifocal tumor formation primarily in the pyloric region. These tumors express diagnostic GIST markers (c-Kit and DOG1) and show significant response to the BRAF inhibitor dabrafenib. This model recapitulates key histopathologic and molecular features of human BRAF-mutant GIST and provides a valuable platform for studying tumor initiation, progression, and therapeutic resistance. Importantly, it allows for preclinical testing of targeted therapies in BRAF GIST, offering new insights into treatment strategies.

This is the first fully penetrant mouse model of BRAF-driven GIST by inducing BRAFV600E in c-Kit+ ICC. This model faithfully recapitulates human BRAF-mutant GIST, enabling mechanistic studies and preclinical testing of targeted therapies, including response to BRAF inhibition with dabrafenib.