Abstract A15: Modeling sporadic gastrointestinal stromal tumor with BRAFV600E mutation

Abstract

Abstract Gastrointestinal stromal tumor (GIST) is the most common subtype of sarcoma, characterized by activating mutations in KIT, PDGFRA, BRAF, N/H/KRAS, and loss of function genetic/epigenetic alterations in NF1, SDH-complex. Despite clinical advances for KIT/PDGFRA-mutant GIST, the scientific and clinical advances for KIT/PDGFRA-wild type GISTs have remained extremely limited due to the lack of model systems. Due to the lack of ICC-lineage specific cre system, modeling for sporadic GIST has not been feasible. ETV1 has recently been described as an ICC and GIST-lineage specific master regulator. Here, using the cre-activated Rosa26CAGGS-LSL-EYFP system, we demonstrate that Etv1CREERT2 preferentially activates cre in the Etv1-expressing ICC lineage by tamoxifen. Using the BrafCA conditional allele for cre-activated BrafV600E, we observed that BrafV600E alone, while leading to development of ICC hyperplasia, is not sufficient to drive GIST tumorigenesis. Combination of BrafV600E activation and Trp53 loss not only gives rise to ICC hyperplasia, but also leads to multifocal GIST-like tumors in mouse GI tract with 100% penetrance. We further demonstrate that the BrafV600E; Tp53-/- sporadic GIST mouse models are amenable for therapeutic intervention and recapitulate clinical responses to RAF inhibitors in human GIST. Our observations provide the first in vivo model for understanding the pathogenesis and therapeutic responses in BRAF-mutant GISTs. Importantly, these observations provide the proof of principle for modeling sporadic GIST in adult mice using the Etv1CREERT2 system and establish the feasibility and utility of establishing model systems for human GISTs that do not have any model systems available for mechanistic studies and therapeutic development. Citation Format: Leili Ran, Devan Murphy, Jessica Sher, Zhen Cao, Shangqian Wang, Edward Walczak, Youxin Guan, Yuanyuan Xie, Shipra Shukla, Yu Zhan, Cristina R. Antonescu, Yu Chen, Ping Chi. Modeling sporadic gastrointestinal stromal tumor with BRAFV600E mutation [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr A15.