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Cancer Discov. 2015 Mar;5(3):304-15. doi: 10.1158/2159-8290.CD-14-0985. Epub 2015 Jan 8.

Combined inhibition of MAP kinase and KIT signaling synergistically destabilizes ETV1 and suppresses GIST tumor growth.

Author information

1
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
2
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Pharmacology, Weill Cornell Medical College, New York, New York.
3
Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
4
Division of Human Health and Medical Science, Graduate School of Kuroshio Science, Kochi University, Nankoku, Kochi, Japan.
5
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Medicine, Weill Cornell Medical College, New York, New York.
6
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Pharmacology, Weill Cornell Medical College, New York, New York. Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York.
7
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
8
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Medicine, Weill Cornell Medical College, New York, New York. Cell and Developmental Biology, Weill Cornell Medical College, New York, New York. chip@mskcc.org cheny1@mskcc.org.

Abstract

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.

SIGNIFICANCE:

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.

PMID:
25572173
PMCID:
PMC4355391
DOI:
10.1158/2159-8290.CD-14-0985
[Indexed for MEDLINE]
Free PMC Article

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