Summary: Activating mutations in the KIT or PDGFRA receptor tyrosine kinase genes are the key oncogenic drivers in the majority of gastrointestinal stromal tumors (GIST), but novel results now show that aberrant kinase signaling is potentiated by a positive feedback circuit that involves the ETS transcription factor ETV1. Targeting ETV1 can disrupt this circuit and re presents a promising new therapeutic approach for the treatment of GISTs. Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract and one of the most common subtypes of sarcomas. Because of their unique molecular properties, GISTs spearheaded the use of targeted therapies in solid tumors, a concept that eventually led to a paradigm shift in oncologic therapy. GISTs were the first solid tumor entity that could successfully be treated with small-molecule inhibitors, specifically tyrosine kinase inhibitors such as imatinib mesylate (Gleevec; ref. 1). This notion came shortly after the discovery that an oncogenic mutation in the KIT (75%-85%) or PDGFRA (platelet-derived growth factor receptor alpha; 5%-7%) gene is the tumor-initiating event in the vast majority of GISTs and leads to constitutive activation of the encoded receptor tyrosine kinase (2, 3). Major responses are seen after first-line treatment with the KIT/PDGFRA inhibitor imatinib, and approximately 85% of patients with metastatic and/or inoperable GIST benefit from this therapy. However, complete tumor remissions are rare, and about 50% of patients experience disease recurrence within 2 years of treatment. There are several reasons for this, including the emergence of secondary mutations in KIT/PDGFRA that confer drug resistance, entry into a state of cellular quiescence, and the potential existence of GIST stem/progenitor cells that express low levels of KIT and are intrinsically imatinib resistant. Given these reasons, it is unlikely that GISTs can be cured with imatinib alone, and additional therapeutic approaches are urgently needed. GISTs are thought to arise from a specialized cell type in the bowel wall, the interstitial cells of Cajal (ICC), or a common progenitor. These cells are present throughout the entire digestive tract, where they serve as pacemaker cells to coordinate peristalsis.
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