TY - JOUR
T1 - HSP90 identified by a proteomic approach as druggable target to reverse platinum resistance in ovarian cancer
AU - Lombardi, Rita
AU - Sonego, Maura
AU - Pucci, Biagio
AU - Addi, Laura
AU - Iannelli, Federica
AU - Capone, Francesca
AU - Alfano, Luigi
AU - Roca, Maria Serena
AU - Milone, Maria Rita
AU - Moccia, Tania
AU - Costa, Alice
AU - Di Gennaro, Elena
AU - Bruzzese, Francesca
AU - Baldassarre, Gustavo
AU - Budillon, Alfredo
N1 - Funding Information:
This work was supported by Italian Ministry of Health Grants (RCR-2019-23669115 and RF-2016-02361040 to GB; GR-2016-02361041 to MS; Ricerca Corrente Funds to Istituto Nazionale Tumori G. Pascale-Progetti M3/6 and M2/14 to AB; CRO-Ricerca Corrente core grant -linea 1 to GB); Regione Campania (POR FESR 2014/2020-Progetto Campania Onco-Terapie CUP: B61G18000470007 to AB); 5X1000 CRO Intramural to GB; Regione Friuli Venezia Giulia (POR-FERS TICHEP grant to GB). Fondazione Italiana per la Ricerca sul Cancro (FIRC)-AIRC supported with a triennial Fellowship MSR (ID 21113) and FI (ID 22648). AC is supported by a PhD fellowship from Fondazione Biasotto. We would like to thank Dr. Rossella De Cecio for pathological analysis of xenograft tumor tissues.
Funding Information:
This work was supported by Italian Ministry of Health Grants (RCR‐2019‐23669115 and RF‐2016‐02361040 to GB; GR‐2016‐02361041 to MS; Ricerca Corrente Funds to Istituto Nazionale Tumori G. Pascale‐Progetti M3/6 and M2/14 to AB; CRO‐Ricerca Corrente core grant ‐linea 1 to GB); Regione Campania (POR FESR 2014/2020‐Progetto Campania Onco‐Terapie CUP: B61G18000470007 to AB); 5X1000 CRO Intramural to GB; Regione Friuli Venezia Giulia (POR‐FERS TICHEP grant to GB). Fondazione Italiana per la Ricerca sul Cancro (FIRC)‐AIRC supported with a triennial Fellowship MSR (ID 21113) and FI (ID 22648). AC is supported by a PhD fellowship from Fondazione Biasotto. We would like to thank Dr. Rossella De Cecio for pathological analysis of xenograft tumor tissues.
Publisher Copyright:
© 2020 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
PY - 2021/4
Y1 - 2021/4
N2 - 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.
AB - 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.
KW - cisplatin
KW - drug resistance
KW - HSP90
KW - ovarian cancer
KW - proteomics
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U2 - 10.1002/1878-0261.12883
DO - 10.1002/1878-0261.12883
M3 - Article
C2 - 33331136
AN - SCOPUS:85100114290
VL - 15
SP - 1005
EP - 1023
JO - Molecular Oncology
JF - Molecular Oncology
SN - 1574-7891
IS - 4
ER -