Dual-specificity protein phosphatase DUSP4 regulates response to MEK inhibition in BRAF wild-type melanoma.
Antineoplastic Combined Chemotherapy Protocols
/ therapeutic use
Benzimidazoles
/ administration & dosage
Docetaxel
/ administration & dosage
Drug Resistance, Neoplasm
/ genetics
Dual-Specificity Phosphatases
/ genetics
Humans
MAP Kinase Kinase Kinases
/ antagonists & inhibitors
Melanoma
/ drug therapy
Mitogen-Activated Protein Kinase Phosphatases
/ genetics
Proto-Oncogene Proteins B-raf
/ genetics
Proto-Oncogene Proteins c-ets
/ genetics
Transcriptome
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
04
07
2019
accepted:
15
11
2019
revised:
30
10
2019
pubmed:
17
12
2019
medline:
22
10
2020
entrez:
17
12
2019
Statut:
ppublish
Résumé
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).
Sections du résumé
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).
Identifiants
pubmed: 31839677
doi: 10.1038/s41416-019-0673-5
pii: 10.1038/s41416-019-0673-5
pmc: PMC7028919
doi:
Substances chimiques
AZD 6244
0
Benzimidazoles
0
ETV4 protein, human
0
Proto-Oncogene Proteins c-ets
0
Docetaxel
15H5577CQD
BRAF protein, human
EC 2.7.11.1
Proto-Oncogene Proteins B-raf
EC 2.7.11.1
MAP Kinase Kinase Kinases
EC 2.7.11.25
Mitogen-Activated Protein Kinase Phosphatases
EC 3.1.3.16
DUSP4 protein, human
EC 3.1.3.48
Dual-Specificity Phosphatases
EC 3.1.3.48
Types de publication
Clinical Trial, Phase II
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
506-516Subventions
Organisme : Cancer Research UK
ID : 14189
Pays : United Kingdom
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