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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Vydané v:	British journal of cancer Ročník 122; číslo 4; s. 506 - 516
Hlavní autori:	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
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	London Nature Publishing Group UK 01.02.2020 Nature Publishing Group
Predmet:	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
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Abstract	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).
AbstractList	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). 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). 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. 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. 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. 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. DOC-MEK (EudraCT no: 2009-018153-23). 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.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.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.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.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.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.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.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.DOC-MEK (EudraCT no: 2009-018153-23).CLINICAL TRIAL REGISTRATIONDOC-MEK (EudraCT no: 2009-018153-23).
Author	Brant, Roz Towers, Christopher Myers, Kevin Macaulay, Valentine Moya Love, Sharon Smith, Paul Hodgson, Darren Richard Cutts, Anthony Asher, Ruth Wise, Adelyn Sharpe, Alan Collins, Linda Willenbrock, Frances Schuh, Anna Middleton, Mark Roy Gupta, Avinash
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GrantInformation_xml	– fundername: FW was supported by funding to the Preclinical Validation Laboratory from the Cancer Research UK Oxford Cancer Research Centre. – fundername: This study was supported by funding from the Oxford NIHR Biomedical Research Centre to AS. – fundername: CT was supported by funding to the Preclinical Validation Laboratory from the Cancer Research UK Oxford Cancer Research Centre. – fundername: The DOC-MEK trial was supported by the collaboration between AstraZeneca and the UK National Cancer Research Network (Grant number: A12154), for which AstraZeneca provided partial funding. DOC-MEK was sponsored by the University of Oxford and was run by the Oncology Clinical Trials (OCTO), Department of Oncology, University of Oxford. This study was supported by funding from the Oxford NIHR Biomedical Research Centre to AS, MRM and VMM, and an Oxfordshire Health Services Research Committee grant to AG. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the United Kingdom’s Department of Health. FW and CT were supported by funding to the Preclinical Validation Laboratory from the Cancer Research UK Oxford Cancer Research Centre. – fundername: Cancer Research UK grantid: 14189 – fundername: ;
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Snippet	Background Aiming to improve treatment options for BRAF wild-type melanoma, we previously conducted the DOC-MEK study of docetaxel with MEK inhibitor (MEKi)... Aiming to improve treatment options for BRAF wild-type melanoma, we previously conducted the DOC-MEK study of docetaxel with MEK inhibitor (MEKi) selumetinib... BackgroundAiming to improve treatment options for BRAF wild-type melanoma, we previously conducted the DOC-MEK study of docetaxel with MEK inhibitor (MEKi)...
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SubjectTerms	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
Title	Dual-specificity protein phosphatase DUSP4 regulates response to MEK inhibition in BRAF wild-type melanoma
URI	https://link.springer.com/article/10.1038/s41416-019-0673-5 https://www.ncbi.nlm.nih.gov/pubmed/31839677 https://www.proquest.com/docview/2357414041 https://www.proquest.com/docview/2327378411 https://pubmed.ncbi.nlm.nih.gov/PMC7028919
Volume	122
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