ETV1-Positive Cells Give Rise to <i>BRAF^V600E</i> -Mutant Gastrointestinal Stromal Tumors.

Abstract

Gastrointestinal stromal tumor (GIST) is the most common subtype of sarcoma. Despite clinical advances in the treatment of <i>KIT/PDGFRA</i>-mutant GIST, similar progress against <i>KIT/PDGFRA</i> wild-type GIST, including mutant BRAF-driven tumors, has been limited by a lack of model systems. ETV1 is a master regulator in the intestinal cells of Cajal (ICC), thought to be the cells of origin of GIST. Here, we present a model in which the ETV1 promoter is used to specifically and inducibly drive Cre recombinase in ICC as a strategy to study GIST pathogenesis. Using a conditional allele for <i>Braf^V600E</i> , a mutation observed in clinical cases of GIST, we observed that <i>Braf^V600E</i> activation was sufficient to drive ICC hyperplasia but not GIST tumorigenesis. In contrast, combining <i>Braf^V600E</i> activation with <i>Trp53</i> loss was sufficient to drive both ICC hyperplasia and formation of multifocal GIST-like tumors in the mouse gastrointestinal tract with 100% penetrance. This mouse model of sporadic GIST model was amenable to therapeutic intervention, and it recapitulated clinical responses to RAF inhibition seen in human GIST. Our work offers a useful <i>in vivo</i> model of human sporadic forms of <i>BRAF</i>-mutant GIST to help unravel its pathogenesis and therapeutic response to novel experimental agents. <i>Cancer Res; 77(14); 3758-65. ©2017 AACR</i>.