title: ASC-J9(®) suppresses castration resistant prostate cancer progression via degrading the enzalutamide-induced androgen receptor mutant AR-F876L.
abstract: Androgen deprivation therapy (ADT) with the newly developed powerful anti-androgen enzalutamide (Enz, also known as MDV3100) has promising therapeutic effects to suppress castration resistant prostate cancer (CRPC) and extending patients' lives an extra 4.8 months. However, most Enz therapy eventually fails with the development of Enz resistance. The detailed mechanisms how CRPC develops Enz resistance remain unclear and may involve multiple mechanisms. Among them, the induction of the androgen receptor (AR) mutant AR-F876L in some CRPC patients may represent one driving force that confers Enz resistance. Here, we demonstrate that the AR degradation enhancer, ASC-J9(®), not only degrades wild-type AR, but also has the ability to target AR-F876L. The consequence of suppressing AR-F876L may then abrogate AR-F876L mediated CRPC cell proliferation and metastasis. Thus, developing ASC-J9(®) as a new therapeutic approach may represent a novel therapy to better suppress CRPC that has already developed Enz resistance.
authors.affiliation: George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Ronghao
authors.initials: R
authors.lastname: Wang
authors.affiliation: George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Wanying
authors.initials: W
authors.lastname: Lin
authors.affiliation: George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Changyi
authors.initials: C
authors.lastname: Lin
authors.affiliation: George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Yin
authors.initials: Y
authors.lastname: Sun
authors.affiliation: George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA; Sex Hormone Research Center, China Medical University and Hospital, Taichung, 404, Taiwan. Electronic address: chang@urmc.rochester.edu.
authors.forename: Chawnshang
authors.initials: C
authors.lastname: Chang
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001549:Benzamides; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D008297:Male; D009154:Mutation; D009362:Neoplasm Metastasis; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000494:pharmacology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D059748:Proteolysis; D011944:Receptors, Androgen / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
chemical_list: D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D001549:Benzamides; D003474:Curcumin; D009570:Nitriles; D010669:Phenylthiohydantoin; D011944:Receptors, Androgen; C471106:ASC-J9 compound; C410798:AR protein, human; C540278:enzalutamide
keywords: AR-F876L; ASC-J9(®); PCa