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Here, we characterized by an unbiased proteomics method three isogenic EOC models of acquired Pt resistance (TOV\u2010112D, OVSAHO, and MDAH\u20102774). Using this approach, we identified several differentially expressed proteins in Pt\u2010resistant (Pt\u2010res) compared to parental cells and the chaperone HSP90 as a central hub of these protein networks. Accordingly, up\u2010regulation of HSP90 was observed in all Pt\u2010res cells and heat\u2010shock protein 90 alpha isoform knockout resensitizes Pt\u2010res cells to cisplatin (CDDP) treatment. Moreover, pharmacological HSP90 inhibition using two different inhibitors [17\u2010(allylamino)\u201017\u2010demethoxygeldanamycin (17AAG) and ganetespib] synergizes with CDDP in killing Pt\u2010res cells in all tested models. Mechanistically, genetic or pharmacological HSP90 inhibition plus CDDP \u2010induced apoptosis and increased DNA damage, particularly in Pt\u2010res cells. Importantly, the antitumor activities of HSP90 inhibitors (HSP90i) were confirmed both\n                    <jats:italic>ex\u00a0vivo<\/jats:italic>\n                    in primary cultures derived from Pt\u2010res EOC patients ascites and\n                    <jats:italic>in\u00a0vivo<\/jats:italic>\n                    in a xenograft model. Collectively, our data suggest an innovative antitumor strategy, based on Pt compounds plus HSP90i, to rechallenge Pt\u2010res EOC patients that might warrant further clinical evaluation.\n                  <\/jats:p>","DOI":"10.1002\/1878-0261.12883","type":"journal-article","created":{"date-parts":[[2020,12,17]],"date-time":"2020-12-17T22:51:54Z","timestamp":1608245514000},"page":"1005-1023","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["HSP90 identified by a proteomic approach as druggable target to reverse platinum resistance in ovarian cancer"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3098-9134","authenticated-orcid":false,"given":"Rita","family":"Lombardi","sequence":"first","affiliation":[{"name":"Experimental Pharmacology Unit\u2010Laboratories of Naples and Mercogliano (AV) Istituto Nazionale per lo Studio e la Cura dei Tumori \u201cFondazione G. 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