Open AccessHSP90 identified by a proteomic approach as druggable target to reverse platinum resistance in ovarian cancer
Author(s) -
Lombardi Rita,
Sonego Maura,
Pucci Biagio,
Addi Laura,
Iannelli Federica,
Capone Francesca,
Alfano Luigi,
Roca Maria Serena,
Milone Maria Rita,
Moccia Tania,
Costa Alice,
Di Gennaro Elena,
Bruzzese Francesca,
Baldassarre Gustavo,
Budillon Alfredo
Publication year - 2021
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12883
Subject(s) - cisplatin , hsp90 , hsp90 inhibitor , cancer research , heat shock protein , ovarian cancer , in vivo , druggability , ex vivo , apoptosis , carboplatin , biology , cancer cell , medicine , cancer , chemotherapy , gene , biochemistry , genetics
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.