Dual-specificity protein phosphatase DUSP4 regulates response to MEK inhibition in BRAF wild-type melanoma.

Content Provider	Europe PMC
Author	Gupta, Avinash Towers, Christopher Willenbrock, Frances Brant, Roz Hodgson, Darren Richard Sharpe, Alan Smith, Paul Cutts, Anthony Schuh, Anna Asher, Ruth Myers, Kevin Love, Sharon Collins, Linda Wise, Adelyn Middleton, Mark Roy Macaulay, Valentine Moya
Abstract	BackgroundAiming to improve treatment options for BRAF wild-type melanoma, we previously conducted the DOC-MEK study of docetaxel with MEK inhibitor (MEKi) selumetinib or placebo, revealing trends to prolongation of progression-free survival (hazard ratio 0.75, P = 0.130), and improved response rates (32% vs 14%, P = 0.059) with docetaxel plus selumetinib. NRAS status did not associate with outcome. Here, the aim was to identify novel biomarkers of response to MEKi.MethodsA MEK 6 gene signature was quantified using NanoString and correlated with clinical outcomes. Two components of the gene signature were investigated by gene silencing in BRAF/NRAS wild-type melanoma cells.ResultsIn melanomas of patients on the selumetinib but not the placebo arm, two gene signature components, dual-specificity protein phosphatase 4 (DUSP4) and ETS translocation variant 4 (ETV4), were expressed more highly in responders than non-responders. In vitro, ETV4 depletion inhibited cell survival but did not influence sensitivity to MEKi selumetinib or trametinib. In contrast, DUSP4-depleted cells showed enhanced cell survival and increased resistance to both selumetinib and trametinib.ConclusionsETV4 and DUSP4 associated with clinical response to docetaxel plus selumetinib. DUSP4 depletion induced MEKi resistance, suggesting that DUSP4 is not only a biomarker but also a mediator of MEKi sensitivity.Clinical Trial RegistrationDOC-MEK (EudraCT no: 2009-018153-23).
ISSN	00070920
Journal	British Journal of Cancer
Volume Number	122
PubMed Central reference number	PMC7028919
Issue Number	4
PubMed reference number	31839677
e-ISSN	15321827
DOI	10.1038/s41416-019-0673-5
Language	English
Publisher	Nature Publishing Group
Publisher Date	2019-12-16
Publisher Place	London
Access Restriction	Open
Rights License	Note This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0). © The Author(s), under exclusive licence to Cancer Research UK 2019
Subject Keyword	Melanoma Cancer therapeutic resistance Cell signalling
Content Type	Text
Resource Type	Article
Subject	Cancer Research Oncology