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Updated: Jan 1, 2026

Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
06:09

Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells

Published on: June 7, 2019

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

Avinash Gupta1,2, Christopher Towers3, Frances Willenbrock3

  • 1Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK. avinash.gupta@christie.nhs.uk.

British Journal of Cancer
|December 17, 2019
PubMed
Abstract

Insights

Dual-specificity protein phosphatase 4 (DUSP4) and ETS translocation variant 4 (ETV4) are novel biomarkers for MEK inhibitor response in BRAF wild-type melanoma. DUSP4 is also a mediator of MEK inhibitor sensitivity.

Area of Science:

  • Oncology
  • Melanoma Research
  • Molecular Biology

Background:

  • BRAF wild-type melanoma treatment options are limited.
  • The DOC-MEK study investigated docetaxel with MEK inhibitor (MEKi) selumetinib, showing trends towards improved progression-free survival and response rates.
  • NRAS status did not impact outcomes in the DOC-MEK study.

Purpose of the Study:

  • To identify novel biomarkers predicting response to MEK inhibitors (MEKi) in BRAF wild-type melanoma.
  • To investigate the role of specific gene signature components in MEKi sensitivity.

Main Methods:

  • Quantified a MEK gene signature using NanoString and correlated it with clinical outcomes.
  • Investigated two gene signature components, DUSP4 and ETV4, using gene silencing in melanoma cell lines.
  • Analyzed gene expression in patient melanomas from the DOC-MEK study.

Main Results:

  • DUSP4 and ETV4 were more highly expressed in responders to selumetinib compared to non-responders.
  • ETV4 depletion inhibited melanoma cell survival but did not affect MEKi sensitivity.
  • DUSP4 depletion enhanced melanoma cell survival and increased resistance to MEKi selumetinib and trametinib.

Conclusions:

  • ETV4 and DUSP4 are associated with clinical response to docetaxel plus selumetinib.
  • DUSP4 depletion induced MEKi resistance, indicating it acts as both a biomarker and a mediator of MEKi sensitivity.

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