title: Inhibition of Hsp90 augments docetaxel therapy in castrate resistant prostate cancer.
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.
authors: Genitourinary Program, Roswell Park Cancer Institute, Buffalo, New York, United States of America; Department of Cancer Prevention and Pathology, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
authors: ShengYu
authors: S
authors: Ku
authors: Genitourinary Program, Roswell Park Cancer Institute, Buffalo, New York, United States of America; Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
authors: Elena
authors: E
authors: Lasorsa
authors: Genitourinary Program, Roswell Park Cancer Institute, Buffalo, New York, United States of America; Department of Cancer Prevention and Pathology, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
authors: Remi
authors: R
authors: Adelaiye
authors: Genitourinary Program, Roswell Park Cancer Institute, Buffalo, New York, United States of America; Department of Cancer Prevention and Pathology, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
authors: Swathi
authors: S
authors: Ramakrishnan
authors: Genitourinary Program, Roswell Park Cancer Institute, Buffalo, New York, United States of America; Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
authors: Leigh
authors: L
authors: Ellis
authors: Genitourinary Program, Roswell Park Cancer Institute, Buffalo, New York, United States of America; Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
authors: Roberto
authors: R
authors: Pili
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D004359:Drug Therapy, Combination; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D012118:Resorcinols / Q000494:pharmacology / Q000627:therapeutic use*; D043823:Taxoids / Q000494:pharmacology / Q000627:therapeutic use*; D014158:Transcription, Genetic; D014183:Transplantation, Heterologous
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D011944:Receptors, Androgen; D012118:Resorcinols; D043823:Taxoids; D000077143:Docetaxel; D046988:Proteasome Endopeptidase Complex