Overcoming Limitations of Cisplatin Therapy by Additional Treatment With the HSP90 Inhibitor Onalespib

Abstract

Rational: Cisplatin based cancer therapy is an affordable and effective standard therapy for several solid cancers, including lung, ovarian and head and neck cancers. However, the clinical use of cisplatin is routinely limited by the development of drug resistance and subsequent therapeutic failure. Therefore, methods of circumventing cisplatin resistance have the potential to increase therapeutic efficiency and dramatically increase overall survival. Cisplatin resistance can be mediated by alterations to the DNA damage response, where multiple components of the repair machinery have been described to be client proteins of HSP90. In the present study, we have investigated whether therapy with the novel HSP90 inhibitor onalespib can potentiate the efficacy of cisplatin and potentially reverse cisplatin resistance in ovarian and head and neck cancer cells. Methods: Cell viability, cancer cell proliferation and migration capacity were evaluated in vitro on models of ovarian and head and neck cancer cells. Western blotting was used to assess the downregulation of HSP90 client proteins and alterations in downstream signaling proteins after exposure to cisplatin and/or onalespib. Induction of apoptosis and DNA damage response were evaluated in both monotherapy and combination therapy groups. Results: Results demonstrate that onalespib enhances the efficiency of cisplatin in a dose-dependent manner. Tumor cells treated with both drugs displayed lower viability and a decreased migration rate compared to vehicle-control cells and cells treated with individual compounds. An increase of DNA double strand breaks was observed in both cisplatin and onalespib treated cells. The damage was highest and most persistent in the combination group, delaying the DNA repair machinery. Further, the cisplatin and onalespib co-treated cells had greater apoptotic activity compared to controls. Conclusion: The results of this study demonstrate that the reduced therapeutic efficacy of cisplatin due to drug-resistance could be overcome by combination treatment with onalespib. We speculate that the increased apoptotic signaling, DNA damage as well as the downregulation of HSP90 client proteins are important mechanisms promoting increased sensitivity to cisplatin treatment.

Heat Shock Protein 90 Triggers Multi-Drug Resistance of Ovarian Cancer via AKT/GSK3β/β-Catenin Signaling

“…Interestingly, recent study suggested that the mechanism of HSP90-mediated resistance could be not only limited to above pathway, but also be involved in the upregulating DNA repair pathways. This is confirmed by the results revealing that Hsp90 inhibitor could cause suppression of DNA repair mechanisms to enhance drugmediated DNA damage in cisplatin-resistant cancer cells, and finally reversed the resistance phenotype (81).…”

Drug-development, dose-selection, rational combinations from bench-to-bedside: are there any lessons worth revisiting?

“…Subsequent to this report, another publication has drawn similar conclusions for the combination of AT13387 with cisplatin, another DNA-damaging agent [ 13 ]. The therapeutic potential of utilizing Hsp90 inhibitors most effectively yet remains to be realized.…”

Hsp90 inhibition sensitizes DLBCL cells to cisplatin

“…However, the lack of increased DNA damage for 17AAG alone and the combination treatment in DB could be explained by the most synergistic concentration being four times lower than in RIVA and OCI-Ly7. In agreement, the combination of cisplatin and an Hsp90 inhibitor has been shown to decrease cell viability and induce DNA damage response in ovarian and head and neck cancer cells [23][24][25].…”