In vitro , ETV4 depletion inhibited cell survival but did not influence sensitivity to MEKi selumetinib or trametinib .
Dual-specificity protein phosphatase DUSP4 regulates response to MEK inhibition in BRAF wild-type melanoma. 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).
### Instruction:
            Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds 
            that can co-occur for the mentioned treatment

            ### Input:
            Dual-specificity protein phosphatase DUSP4 regulates response to MEK inhibition in BRAF wild-type melanoma. 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).

            ### Response:
            selumetinib, trametinib
            