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Specifically, the combined use of drugs with different mechanisms of action can reduce the probability of selecting resistant clones. To identify agents active against melanoma cells, we screened a library of 349 anti\u2010cancer compounds, currently in clinical use or trials, and selected <jats:styled-content style=\"fixed-case\">PIK<\/jats:styled-content>\u201075, an inhibitor of the phosphatidylinositol 3\u2010kinase\/protein kinase B (<jats:styled-content style=\"fixed-case\">PI<\/jats:styled-content>3K\/<jats:styled-content style=\"fixed-case\">AKT<\/jats:styled-content>) pathway, as the \u2018top active\u2019 drug. <jats:styled-content style=\"fixed-case\">PIK<\/jats:styled-content>\u201075 was then used alone or in combination with vemurafenib, the first BRAF inhibitor approved for patients with melanoma harboring <jats:styled-content style=\"fixed-case\">BRAF<\/jats:styled-content> mutations. We identified a combined dose of <jats:styled-content style=\"fixed-case\">PIK<\/jats:styled-content>\u201075 and vemurafenib that inhibited both the <jats:styled-content style=\"fixed-case\">PI<\/jats:styled-content>3K\/<jats:styled-content style=\"fixed-case\">AKT<\/jats:styled-content> and mitogen\u2010activated protein kinase pathways, thereby overcoming any compensatory activation. In view of the important tumor suppressor function induced by restoring expression of microRNA (miR)\u2010126 in metastatic melanoma cells, we examined whether miR\u2010126 has a synergistic role when included in a triple combination alongside <jats:styled-content style=\"fixed-case\">PIK<\/jats:styled-content>\u201075 and vemurafenib. We found that enforced expression of miR\u2010126 (which alone can reduce tumorigenicity) significantly increased <jats:styled-content style=\"fixed-case\">PIK<\/jats:styled-content>\u201075 activity when used as either a single agent or in combination with vemurafenib. Interestingly, <jats:styled-content style=\"fixed-case\">PIK<\/jats:styled-content>\u201075 proved to be effective against early passage cell lines derived from patients\u2019 biopsies and on melanoma cell lines resistant to either vemurafenib or dabrafenib, thus suggesting that it potentially has the capability to overcome drug resistance. Finally, the synergistic role played by miR\u2010126 in combination with vemurafenib and\/or <jats:styled-content style=\"fixed-case\">PIK<\/jats:styled-content>\u201075 was demonstrated <jats:italic>in\u00a0vivo<\/jats:italic> in mouse xenograft models, in which tumor growth inhibition was associated with increased apoptosis. These results not only show the efficacy of <jats:styled-content style=\"fixed-case\">PIK<\/jats:styled-content>\u201075 and vemurafenib co\u2010treatment but also indicate that restoration of miR\u2010126 expression in advanced melanoma can enhance their antitumor activity, which may possibly allow dose reduction to decrease adverse events without reducing the therapeutic benefits.<\/jats:p>","DOI":"10.1002\/1878-0261.12506","type":"journal-article","created":{"date-parts":[[2019,5,22]],"date-time":"2019-05-22T11:20:10Z","timestamp":1558524010000},"page":"1836-1854","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Joint action of miR\u2010126 and MAPK\/PI3K inhibitors against metastatic melanoma"],"prefix":"10.1002","volume":"13","author":[{"given":"Francesca","family":"Pedini","sequence":"first","affiliation":[{"name":"Department of Oncology and Molecular Medicine Istituto Superiore di Sanit\u00e0 Rome 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