Novel therapeutics development and mechanisms of therapeutic resistance in gastrointestinal stromal tumor (GIST)

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RP-1: Novel Therapeutics Development and Mechanisms of Therapeutic Resistance in GIST ABSTRACT Gastrointestinal stromal tumor (GIST) represents one of the most prevalent sarcoma subtypes and is the most common mesenchymal neoplasm of the GI tract. Most GISTs harbor activating oncogenic “driver” mutations in receptor tyrosine kinases, e.g. KIT or PDGFRA. Among KIT/PDGFRA wild-type GISTs, the majority harbor loss-of-function defects in the mitochondrial succinate dehydrogenase (SDH) complex, a component of the Krebs cycle. KIT/PDGFRA-mutant and SDH-deficient GISTs represent molecularly distinct groups, with distinct clinical behaviors. We have recently identified ETV1 as a master regulator for the lineage specification and normal development of the GIST precursor cells, the interstitial cells of Cajal. Importantly, ETV1 is required for the growth and survival of imatinib-sensitive and -resistant GISTs in vitro and for tumor initiation and maintenance in vivo. We hypothesize ETV1 is a novel therapeutic target that is critical for the shared lineage-dependent survival of both imatinib-sensitive and -resistant GISTs. In this project, we propose a comprehensive study to understand the regulation of ETV1 protein stability, and to develop novel therapeutic strategies targeting ETV1 protein stability using various pre-clinical GIST models. In parallel, we will investigate clinical samples from prior and ongoing clinical trials designed to target ETV1 protein stability to better understand the molecular mechanisms of therapeutic resistance. Moreover, targeted sequencing using custom IMPACT panels will be used on these matched pre- and post-therapy biopsy samples from the on-going phase Ib/II trials using imatinib in combination with MEK162 to elucidate mechanism of drug resistance. This investigation will leverage comprehensive and multidisciplinary approaches, including biochemical, state-of-the-art genomics, and genetic approaches in in vitro and in vivo models as well as patient tumor samples derived from current GIST clinical trials. The therapeutic strategies identified here may benefit other ETV1-dependent malignancies. Lastly, since there are no in vitro and in vivo models for focused mechanistic and therapeutic investigation of SDH-deficient GISTs, we will generate cell line models through novel gene editing technology, such as CRISPR and CRISPRi, in established GIST cell lines as well as in human mesenchymal progenitor cells that are committed to the interstitial cells of Cajal lineage. We will also develop in vivo murine models of SDH-deficient GISTs for focused evaluation of therapeutics specifically targeting SDH deficiency that may benefit other SDH- deficient malignancies beyond GIST.