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

Abstract

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.

Multiomic analysis identifies CPT1A as a potential therapeutic target in platinum-refractory, high-grade serous ovarian cancer

“…24 Most recently, differentially expressed proteins were identified between platinum-resistant OC cell lines (TOV-112D, OVSAHO, and MDAH-2774) and their parental cells, and HSP90 was implicated as a central hub of these protein networks. 25 To date, no multiomic profiling of the dynamic response of cancer cells to platinum has been reported.…”

Maggot Extract Inhibits Cell Migration and Tumor Growth by Targeting HSP90AB1 in Ovarian Cancer

“…In addition, HSP90 has been reported to be overexpressed in Pt-resistant cancer cells, suggesting its potential role in the resistance mechanism. HSP90 inhibition in combination with cisplatin has a synergistic antitumor effect in drug-resistant epithelial ovarian cancer cells [ 37 ]. HSP90AB1 is one subtype of the HSP90 family, which is related to ATPase activity in cancer cells, and part of its function is to promote cell growth, metastases, invasion, and immune response [ 38 , 39 , 40 ].…”

“…In turn, inhibition of HSP90AB1 further promotes ME-induced ovarian cancer cell apoptosis. Previous studies have consistently demonstrated that HSP90 as a druggable target reverses Pt resistance in ovarian cancer [ 11 , 37 ]. In addition, knockdown of HSP90 significantly inhibits cell proliferation in H08910 ovarian cancer cells [ 41 ].…”

Targeting Heat-Shock Protein 90 in Cancer: An Update on Combination Therapy

“…Furthermore, a triple combination of SNX-5422, carboplatin, and paclitaxel followed by maintenance SNX-5422 therapy showed substantial tolerance and antitumor activity against NSCLC [ 88 ]. Other studies can be seen in Table 2 [ 65 , 66 , 67 ].…”