Abstract
Oncogenic client-proteins of the chaperone Heat shock protein 90 (HSP90) insure unlimited tumor growth and are involved in resistance to chemo- and radiotherapy. The HSP90 inhibitor Onalespib initiates the degradation of oncoproteins, and might also act as a radiosensitizer. The aim of this study was therefore to evaluate the efficacy of Onalespib in combination with external beam radiotherapy in an in vitro and in vivo approach. Onalespib downregulated client proteins, lead to increased apoptosis and caused DNA-double-strands. Monotherapy and combination with radiotherapy reduced colony formation, proliferation and migration assessed in radiosensitive HCT116 and radioresistant A431 cells. In vivo, a minimal treatment regimen for 3 consecutive days of Onalespib (3 × 10 mg/kg) doubled survival, whereas Onalespib with radiotherapy (3 × 2 Gy) caused a substantial delay in tumor growth and prolonged the survival by a factor of 3 compared to the HCT116 xenografted control group. Our results demonstrate that Onalespib exerts synergistic anti-cancer effects when combined with radiotherapy, most prominent in the radiosensitive cell models. We speculate that the depletion and downregulation of client proteins involved in signalling, migration and DNA repair mechanisms is the cause. Thus, individually, or in combination with radiotherapy Onalespib inhibits tumor growth and has the potential to improve radiotherapy outcomes, prolonging the overall survival of cancer patients.
Highlights
Oncogenic client-proteins of the chaperone Heat shock protein 90 (HSP90) insure unlimited tumor growth and are involved in resistance to chemo- and radiotherapy
In this study we investigated the efficacy of the new anti-HSP90 drug Onalespib in combination with external beam radiation therapy
As evident from the survival and viability analyses, HCT116 cells were significantly more sensitive to the single and combination treatments in comparison to A431 cells (Fig. 1A,B), which is in line with previous studies, where radiotherapy and Onalespib treatment acted in an additive manner for A431 cells and in a synergistic for HCT1169
Summary
Oncogenic client-proteins of the chaperone Heat shock protein 90 (HSP90) insure unlimited tumor growth and are involved in resistance to chemo- and radiotherapy. Our results demonstrate that Onalespib exerts synergistic anti-cancer effects when combined with radiotherapy, most prominent in the radiosensitive cell models. In combination with radiotherapy Onalespib inhibits tumor growth and has the potential to improve radiotherapy outcomes, prolonging the overall survival of cancer patients. High initial cancer treatment response rates are often followed by the development of resistance to the therapy and eventual recurrence of the disease. Combining anti-cancer treatments not sequentially, but simultaneously is an appealing approach to maintain clinical efficacy and to overcome the development of therapy resistance[2]. Inhibition of HSP90 as a strategy to control cancer is appealing since it leads to downregulation of multiple oncogenic proteins and pathways simultaneously. In 2017 alone, 17 clinical trials assessing anti-HSP90 drugs have been active, of which 7 were evaluating the inhibitor Onalespib (AT13387; NCT01712217, NCT02503709, NCT02097225, NCT02572453, NCT02381535, NCT02535338, NCT02474173)[6]
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