Molecular Oncology (Apr 2021)

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

  • Rita Lombardi,
  • Maura Sonego,
  • Biagio Pucci,
  • Laura Addi,
  • Federica Iannelli,
  • Francesca Capone,
  • Luigi Alfano,
  • Maria Serena Roca,
  • Maria Rita Milone,
  • Tania Moccia,
  • Alice Costa,
  • Elena Di Gennaro,
  • Francesca Bruzzese,
  • Gustavo Baldassarre,
  • Alfredo Budillon

DOI
https://doi.org/10.1002/1878-0261.12883
Journal volume & issue
Vol. 15, no. 4
pp. 1005 – 1023

Abstract

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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.

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