Abstract
First line treatment of patients with castrate resistant prostate cancer (CRPC) primarily involves administration of docetaxel chemotherapy. Unfortunately, resistance to docetaxel therapy is an ultimate occurrence. Alterations in androgen receptor (AR) expression and signaling are associated mechanisms underlying resistance to docetaxel treatment in CRPC. Heat shock protein 90 (Hsp90) is a molecular chaperone, which regulates the activation, maturation and stability of critical signaling proteins involved in prostate cancer, including the AR. This knowledge and recent advances in compound design and development have highlighted Hsp90 as an attractive therapeutic target for the treatment of CRPC. We recently reported the development of a MYC-CaP castrate resistant (MYC-CaP/CR) transplant tumor model, which expresses amplified wild type AR. Within, we report that a second generation Hsp90 inhibitor, NVP-AUY922, inhibits cell growth and significantly induces cell death in MYC-CaP/CR and Pten-CaP/cE2 cell lines. NVP-AUY922 induced proteasome degradation of AR, though interestingly does not require loss of AR protein to inhibit AR transcriptional activity. Further, NVP-AUY922 increased docetaxel toxicity in MYC-CaP/CR and Pten-CaP/cE2 cell lines in vitro. Finally, NVP-AUY922/docetaxel combination therapy in mice bearing MYC-CaP/CR tumors resulted in greater anti-tumor activity compared to single treatment. This study demonstrates that NVP-AUY922 elicits potent activity towards AR signaling and augments chemotherapy response in a mouse model of CRPC, providing rationale for the continued clinical development of Hsp90 inhibitors in clinical trials for treatment of CRPC patients.
Highlights
Castrate resistant prostate cancer (CRPC) is an incurable and aggressive prostate cancer (PCa) phenotype
The effect of AUY922 on androgen receptor (AR) transcriptional activity was assessed by using MYC-CaP/ CR cells with stable expression of a luciferase reporter driven by androgen response elements (ARE-Luc)
MYC-CaP/CR/ARELuc cells were incubated with increasing concentrations of AUY922 and 1 nM R1881 concurrently overnight or pretreated with 1 nM R1881 for 4 hours followed by increasing concentrations of AUY922 overnight
Summary
Castrate resistant prostate cancer (CRPC) is an incurable and aggressive prostate cancer (PCa) phenotype. The second line cabazitaxel [2], the immunotherapy sipuluecel-T [3], the androgen synthesis inhibitor abiraterone acetate [4],the AR antagonist enzalutamide [5], and radium-223 [6] have all received recent FDA approval for the treatment of CRPC. These new therapies have expanded the treatments options for patients, sustainable suppression of CRPC growth still remains a primary challenge and new treatment strategies are still required. This can create avenues for monotherapy treatment of docetaxel resistance CRPC or potentially re-sensitize CRPC patients to docetaxel therapy with novel combination strategies
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