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- Title
Dual-specificity protein phosphatase DUSP4 regulates response to MEK inhibition in BRAF wild-type melanoma.
- 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
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusions: </bold>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.<bold>Clinical Trial Registration: </bold>DOC-MEK (EudraCT no: 2009-018153-23).
- Subjects
THERAPEUTIC use of antineoplastic agents; PROTEINS; RESEARCH; MELANOMA; HETEROCYCLIC compounds; RESEARCH methodology; PHOSPHATASES; EVALUATION research; MEDICAL cooperation; COMPARATIVE studies; GENE expression profiling; TRANSFERASES; RESEARCH funding; DRUG resistance in cancer cells
- Publication
British Journal of Cancer, 2020, Vol 122, Issue 4, p506
- ISSN
0007-0920
- Publication type
journal article
- DOI
10.1038/s41416-019-0673-5