Data from Combined Inhibition of MAP Kinase and KIT Signaling Synergistically Destabilizes ETV1 and Suppresses GIST Tumor Growth

Abstract

<div>Abstract<p>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 <i>Kit</i> activation and <i>Etv1</i> ablation, we demonstrate that ETV1 is required for GIST initiation and proliferation <i>in vivo</i>, 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 <i>KIT</i> expression. Combined targeting of ETV1 stability by imatinib and MEK162 resulted in increased growth suppression <i>in vitro</i> and complete tumor regression <i>in vivo</i>. The combination strategy to target ETV1 may provide an effective therapeutic strategy in GIST clinical management.</p><p><b>Significance:</b> 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. <i>Cancer Discov; 5(3); 304–15. ©2015 AACR</i>.</p><p>See related commentary by Duensing, p. 231</p><p>This article is highlighted in the In This Issue feature, p. 213</p></div>