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

Abstract

UNLABELLED: 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. SIGNIFICANCE: 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.