title: Mechanisms of acquired resistance to androgen receptor targeting drugs in castration-resistant prostate cancer.
abstract: After initial response to androgen receptor (AR) targeting drugs abiraterone or enzalutamide, most patients develop progressive disease and therefore, castration resistant prostate cancer remains a terminal disease. Multiple mechanisms underlying acquired resistance have been postulated. Intratumoral androgen synthesis may resume after abiraterone treatment. A point mutation in the ligand-binding domain of AR may confer resistance to enzalutamide. Emergence of AR splice variants lacking the ligand-binding domain may mediate resistance to abiraterone and enzalutamide. Steroid receptors such as glucocorticoid receptor may substitute for AR. Drugs with novel mechanisms of action or combination therapy, along with biomarkers for patient selection, may be needed to improve the therapy of castration resistant prostate cancer.
authors.affiliation: Department of Medicine, Division of Hematology and Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: David D
authors.initials: DD
authors.lastname: Chism
authors.forename: Dinuka
authors.initials: D
authors.lastname: De Silva
authors.forename: Young E
authors.initials: YE
authors.lastname: Whang
mesh_terms: D059002:Androgen Receptor Antagonists / Q000008:administration & dosage*; D016503:Drug Delivery Systems / Q000379:methods* / Q000639:trends; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D008297:Male; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*
chemical_list: C410798:AR protein, human; D059002:Androgen Receptor Antagonists; D011944:Receptors, Androgen
keywords: abiraterone; acquired drug resistance; androgen receptor; androgen receptor splice variants; enzalutamide; glucocorticoid receptor; intratumoral androgen synthesis; prostate cancer