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

Abstract

UNLABELLED:

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.

• Authors: Leili Ran, Inna Sirota, Zhen Cao, Devan Murphy, Yuedan Chen, Shipra Shukla, Yuanyuan Xie, Michael C Kaufmann, Dong Gao, Sinan Zhu, Ferdinando Rossi, John Wongvipat, Takahiro Taguchi, William D Tap, Ingo K Mellinghoff, Peter Besmer, Cristina R Antonescu, Yu Chen, Ping Chi
• Journal: Cancer discovery (Cancer Discov) Vol. 5 Issue 3 Pg. 304-15 (Mar 2015) ISSN: 2159-8290 [Electronic] United States
• PMID: 25572173 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• DNA-Binding Proteins
• ETV1 protein, human
• Protein Kinase Inhibitors
• Transcription Factors
• Proto-Oncogene Proteins c-kit
• Mitogen-Activated Protein Kinases

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Transformation, Neoplastic (genetics, metabolism)
• DNA-Binding Proteins (metabolism)
• Disease Models, Animal
• Drug Synergism
• Gastrointestinal Stromal Tumors (genetics, metabolism, pathology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Mice
• Mitogen-Activated Protein Kinases (metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-kit (metabolism)
• Signal Transduction (drug effects)
• Transcription Factors (metabolism)
• Tumor Burden (drug effects, genetics)
• Xenograft Model Antitumor Assays