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Ref Type Journal Article
PMID (25572173)
Authors Ran L, Sirota I, Cao Z, Murphy D, Chen Y, Shukla S, Xie Y, Kaufmann MC, Gao D, Zhu S, Rossi F, Wongvipat J, Taguchi T, Tap WD, Mellinghoff IK, Besmer P, Antonescu CR, Chen Y, Chi P
Title Combined inhibition of MAP kinase and KIT signaling synergistically destabilizes ETV1 and suppresses GIST tumor growth.
Abstract Text Gastrointestinal stromal tumor (GIST), originating from the interstitial cells of Cajal (ICC), is characterized by frequent activating mutations of the KIT receptor tyrosine kinase. Despite the clinical success of imatinib, which targets KIT, most patients with advanced GIST develop resistance and eventually die of the disease. The ETS family transcription factor ETV1 is a master regulator of the ICC lineage. Using mouse models of Kit activation and Etv1 ablation, we demonstrate that ETV1 is required for GIST initiation and proliferation in vivo, validating it as a therapeutic target. We further uncover a positive feedback circuit where MAP kinase activation downstream of KIT stabilizes the ETV1 protein, and ETV1 positively regulates KIT expression. Combined targeting of ETV1 stability by imatinib and MEK162 resulted in increased growth suppression in vitro and complete tumor regression in vivo. The combination strategy to target ETV1 may provide an effective therapeutic strategy in GIST clinical management.ETV1 is a lineage-specific oncogenic transcription factor required for the growth and survival of GIST. We describe a novel strategy of targeting ETV1 protein stability by the combination of MEK and KIT inhibitors that synergistically suppress tumor growth. This strategy has the potential to change first-line therapy in GIST clinical management.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KIT V560del gastrointestinal stromal tumor predicted - sensitive Imatinib Preclinical Actionable In a preclinical study, Gleevec (imatinib) treatment resulted in inhibition of tumor proliferation in a mouse model of gastrointestinal stromal tumor harboring KIT V558del (corresponding to V560del in human) (PMID: 25572173). 25572173
KIT V560del gastrointestinal stromal tumor predicted - sensitive Binimetinib + Imatinib Preclinical Actionable In a preclinical study, combination treatment with Gleevec (imatinib) and Mektovi (binimetinib) resulted in greater inhibition of tumor growth than either agent alone in a mouse model of gastrointestinal stromal tumor harboring KIT V558del (corresponding to V560del in human) (PMID: 25572173). 25572173