HSP90 identified by a proteomic approach as druggable target to reverse platinum resistance in ovarian cancer: Molecular Oncology

R. Lombardi, M. Sonego, B. Pucci, L. Addi, F. Iannelli, F. Capone, L. Alfano, M.S. Roca, M.R. Milone, T. Moccia, A. Costa, E. Di Gennaro, F. Bruzzese, G. Baldassarre, A. Budillon

Research output: Contribution to journalArticlepeer-review


Acquired resistance to platinum (Pt)-based therapies is an urgent unmet need in the management of epithelial ovarian cancer (EOC) patients. Here, we characterized by an unbiased proteomics method three isogenic EOC models of acquired Pt resistance (TOV-112D, OVSAHO, and MDAH-2774). Using this approach, we identified several differentially expressed proteins in Pt-resistant (Pt-res) compared to parental cells and the chaperone HSP90 as a central hub of these protein networks. Accordingly, up-regulation of HSP90 was observed in all Pt-res cells and heat-shock protein 90 alpha isoform knockout resensitizes Pt-res cells to cisplatin (CDDP) treatment. Moreover, pharmacological HSP90 inhibition using two different inhibitors [17-(allylamino)-17-demethoxygeldanamycin (17AAG) and ganetespib] synergizes with CDDP in killing Pt-res cells in all tested models. Mechanistically, genetic or pharmacological HSP90 inhibition plus CDDP -induced apoptosis and increased DNA damage, particularly in Pt-res cells. Importantly, the antitumor activities of HSP90 inhibitors (HSP90i) were confirmed both ex vivo in primary cultures derived from Pt-res EOC patients ascites and in vivo in a xenograft model. Collectively, our data suggest an innovative antitumor strategy, based on Pt compounds plus HSP90i, to rechallenge Pt-res EOC patients that might warrant further clinical evaluation. © 2020 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
Original languageEnglish
Pages (from-to)1005-1023
Number of pages19
JournalMol. Oncol.
Issue number4
Publication statusPublished - 2021


  • cisplatin
  • drug resistance
  • HSP90
  • ovarian cancer
  • proteomics
  • carboplatin
  • DNA
  • ganetespib
  • heat shock protein 90
  • heterogeneous nuclear ribonucleoprotein K
  • phosphoglycerate dehydrogenase
  • tanespimycin
  • antineoplastic agent
  • benzoquinone derivative
  • macrocyclic lactam
  • platinum
  • triazole derivative
  • animal cell
  • animal experiment
  • animal model
  • animal tissue
  • antineoplastic activity
  • antiproliferative activity
  • apoptosis
  • Article
  • ascites
  • BJ1-hTERT cell line
  • cancer combination chemotherapy
  • cancer resistance
  • cancer survival
  • colony formation
  • controlled study
  • CRISPR-CAS9 system
  • DNA damage
  • drug dose reduction
  • drug megadose
  • drug potentiation
  • drug targeting
  • ex vivo study
  • female
  • human
  • human cell
  • IC50
  • in vivo study
  • low drug dose
  • monotherapy
  • mouse
  • nonhuman
  • ovary carcinoma
  • priority journal
  • protein expression
  • protein phosphorylation
  • TOV-112D cell line
  • tumor volume
  • tumor xenograft
  • Western blotting
  • animal
  • drug screening
  • nonobese diabetic mouse
  • nude mouse
  • ovary tumor
  • SCID mouse
  • tumor cell line
  • Animals
  • Antineoplastic Agents
  • Benzoquinones
  • Carcinoma, Ovarian Epithelial
  • Cell Line, Tumor
  • Cisplatin
  • Drug Resistance, Neoplasm
  • Female
  • HSP90 Heat-Shock Proteins
  • Humans
  • Lactams, Macrocyclic
  • Mice, Inbred NOD
  • Mice, Nude
  • Mice, SCID
  • Ovarian Neoplasms
  • Platinum
  • Proteomics
  • Triazoles
  • Xenograft Model Antitumor Assays


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