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

Background Aiming 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 ra...

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Published in:British journal of cancer Vol. 122; no. 4; pp. 506 - 516
Main Authors: 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
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 01.02.2020
Nature Publishing Group
Subjects:
631/67/1059/2326
631/80/86
692/4028/67/1813/1634
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Benzimidazoles - administration & dosage
Biomarkers
Biomedical and Life Sciences
Biomedicine
Cancer Research
Cell survival
Clinical trials
Docetaxel - administration & dosage
Drug Resistance
Drug Resistance, Neoplasm - genetics
Dual-Specificity Phosphatases - genetics
Epidemiology
Gene silencing
Humans
Inhibitor drugs
MAP Kinase Kinase Kinases - antagonists & inhibitors
MEK inhibitors
Melanoma
Melanoma - drug therapy
Melanoma - genetics
Mitogen-Activated Protein Kinase Phosphatases - genetics
Molecular Medicine
Oncology
Phosphatase
Protein phosphatase
Proto-Oncogene Proteins B-raf - genetics
Proto-Oncogene Proteins c-ets - genetics
Transcriptome
ISSN:0007-0920, 1532-1827, 1532-1827
Online Access:Get full text
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Summary:Background Aiming 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. Methods A 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. Results In 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. Conclusions ETV4 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 Registration DOC-MEK (EudraCT no: 2009-018153-23).
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ISSN:0007-0920
1532-1827
1532-1827
DOI:10.1038/s41416-019-0673-5