{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T21:08:25Z","timestamp":1785186505141,"version":"3.55.0"},"reference-count":31,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,6,3]],"date-time":"2022-06-03T00:00:00Z","timestamp":1654214400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>The mammalian target of rapamycin (mTOR) inhibitor everolimus has been shown to display antiproliferative effects on a wide spectrum of tumors. <jats:italic>In vitro<\/jats:italic> studies demonstrated that everolimus inhibited pituitary neuroendocrine tumor (PitNET) cell growth in a subset of patients. Sensitivity to everolimus is reduced by an escape mechanism that increases AKT phosphorylation (p-AKT), leading to pro-survival pathway activation. Dopamine receptor type 2 (DRD2) mediates a reduction of p-AKT in a subgroup of non-functioning PitNETs (NF-PitNETs) and in prolactin-secreting tumor cells (MMQ cells) through a \u03b2-arrestin 2-dependent mechanism. The aim of this study was to investigate the efficacy of everolimus combined with DRD2 agonist cabergoline in reducing NF-PitNET primary cells and MMQ cell proliferation and to evaluate AKT phosphorylation and a possible role of \u03b2-arrestin 2. We found that 9 out of 14 NF-PitNETs were resistant to everolimus, but the combined treatment with cabergoline inhibited cell proliferation in 7 out of 9 tumors (-31.4 \u00b1 9.9%, <jats:italic>p<\/jats:italic> &amp;lt; 0.001 <jats:italic>vs<\/jats:italic>. basal) and reduced cyclin D3 expression. In the everolimus-unresponsive NF-PitNET group, everolimus determined a significant increase of p-AKT\/total-AKT ratio (2.1-fold, <jats:italic>p<\/jats:italic> &amp;lt; 0.01, <jats:italic>vs<\/jats:italic>. basal) that was reverted by cabergoline cotreatment. To investigate the molecular mechanism involved, we used MMQ cells as a model of everolimus escape mechanism. Indeed everolimus did not affect MMQ cell proliferation and increased the p-AKT\/total-AKT ratio (+1.53 \u00b1 0.24-fold, <jats:italic>p<\/jats:italic> &amp;lt; 0.001 <jats:italic>vs<\/jats:italic>. basal), whereas cabergoline significantly reduced cell proliferation (-22.8 \u00b1 6.8%, <jats:italic>p<\/jats:italic> &amp;lt; 0.001 <jats:italic>vs<\/jats:italic>. basal) and p-AKT. The combined treatment of everolimus and cabergoline induced a reduction of both cell proliferation (-34.8 \u00b1 18%, <jats:italic>p<\/jats:italic> &amp;lt; 0.001 <jats:italic>vs<\/jats:italic>. basal and <jats:italic>p<\/jats:italic> &amp;lt; 0.05 <jats:italic>vs<\/jats:italic>. cabergoline alone) and p-AKT\/total-AKT ratio (-34.5 \u00b1 14%, <jats:italic>p<\/jats:italic> &amp;lt; 0.001 <jats:italic>vs<\/jats:italic>. basal and <jats:italic>p<\/jats:italic> &amp;lt; 0.05 <jats:italic>vs<\/jats:italic>. cabergoline alone). To test \u03b2-arrestin 2 involvement, silencing experiments were performed in MMQ cells. Our data showed that the lack of \u03b2-arrestin 2 prevented the everolimus and cabergoline cotreatment inhibitory effects on both p-AKT and cell proliferation. In conclusion, this study revealed that cabergoline might overcome the everolimus escape mechanism in NF-PitNETs and tumoral lactotrophs by inhibiting upstream AKT activation. The co-administration of cabergoline might improve mTOR inhibitor antitumoral activity, paving the way for a potential combined therapy in \u03b2-arrestin 2-expressing NF-PitNETs or other PitNETs resistant to conventional treatments.<\/jats:p>","DOI":"10.3389\/fendo.2022.867822","type":"journal-article","created":{"date-parts":[[2022,6,3]],"date-time":"2022-06-03T10:01:52Z","timestamp":1654250512000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["DRD2 Agonist Cabergoline Abolished the Escape Mechanism Induced by mTOR Inhibitor Everolimus in Tumoral Pituitary Cells"],"prefix":"10.3389","volume":"13","author":[{"given":"Federica","family":"Mangili","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuela","family":"Esposito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donatella","family":"Treppiedi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa","family":"Catalano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giusy","family":"Marra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genesio","family":"Di Muro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna 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