Novel Hsp90 inhibitor NVP-AUY922 radiosensitizes prostate cancer cells

Abstract

Outcomes for poor-risk localized prostate cancers treated with radiation are still insufficient. Targeting the "non-oncogene" addiction or stress response machinery is an appealing strategy for cancer therapeutics. Heat-shock-protein-90 (Hsp90), an integral member of this machinery, is a molecular chaperone required for energy-driven stabilization and selective degradation of misfolded "client" proteins, that is commonly overexpressed in tumor cells. Hsp90 client proteins include critical components of pathways implicated in prostate cancer cell survival and radioresistance, such as androgen receptor signaling and the PI3K-Akt-mTOR pathway. We examined the effects of a novel non-geldanamycin Hsp90 inhibitor, AUY922, combined with radiation (RT) on two prostate cancer cell lines, Myc-CaP and PC3, using in vitro assays for clonogenic survival, apoptosis, cell cycle distribution, γ-H2AX foci kinetics and client protein expression in pathways important for prostate cancer survival and radioresistance. We then evaluated tumor growth delay and effects of the combined treatment (RT-AUY922) on the PI3K-Akt-mTOR and AR pathways in a hind-flank tumor graft model. We observed that AUY922 caused supra-additive radiosensitization in both cell lines at low nanomolar doses with enhancement ratios between 1.4-1.7 (p < 0.01). RT-AUY922 increased apoptotic cell death compared with either therapy alone, induced G 2-M arrest and produced marked changes in client protein expression. These results were confirmed in vivo, where RT-AUY922 combination therapy produced supra-additive tumor growth delay compared with either therapy by itself in Myc-CaP and PC3 tumor grafts (both p < 0.0001). Our data suggest that combined RT-AUY922 therapy exhibits promising activity against prostate cancer cells, which should be investigated in clinical studies.

Co-targeting AR and HSP90 suppresses prostate cancer cell growth and prevents resistance mechanisms

“…While more potent inhibitors such as AUY922 are currently being developed and show promise as single agents (Samuel et al 2010, Centenera et al 2012, recent evidence of additive or synergistic activity between 17-AAG and cytotoxic agents or specific molecular therapeutics provides a promising new avenue of clinical development for this drug . In preclinical prostate cancer studies, 17-AAG or AUY922 combined with ionizing radiation has demonstrated supra-additive reductions in tumor growth and clonogenicity (Enmon et al 2003, Ochel & Gademann 2006, Gandhi et al 2013. Likewise, AUY922 sensitized CRPC prostate cancer cells lines to treatment with docetaxel chemotherapy (Ku et al 2014).…”

Hsp90 Inhibitor Ganetespib Sensitizes Non–Small Cell Lung Cancer to Radiation but Has Variable Effects with Chemoradiation

“…Checkpoint arrest mainly at G2/M phase has also been suggested as a cause of radiosensitization with Hsp90 inhibitors (19–24, 36). Radiosensitization effect in vivo by Hsp90 inhibitors has also been demonstrated (14, 21, 23). These data strongly suggest that targeting Hsp90 with its inhibitors represents a promising strategy for enhancing the sensitivity of cancer cells to radiation (19–24).…”

Heat-Shock Protein 90 Inhibitors: Will They Ever Succeed as Chemotherapeutics?

“…Alternatives to 17-AAG have been developed [19], and several promising molecules, including AUY922 [5] and Ganetspib (STA-9090) [20], are in current clinical trials as monotherapies. However, there are still concerns about the HSR triggered by blocking the ATP-Hsp90 interaction, as it provides tumor cells an opportunity to survive.…”

“…Over the past 10 years, 15 different Hsp90 inhibitors have been tested in clinical trials [3][4][5]. However, only three remain active as mono-chemotherapy regiments [6].…”