title: Overcoming mutation-based resistance to antiandrogens with rational drug design.
abstract: The second-generation antiandrogen enzalutamide was recently approved for patients with castration-resistant prostate cancer. Despite its success, the duration of response is often limited. For previous antiandrogens, one mechanism of resistance is mutation of the androgen receptor (AR). To prospectively identify AR mutations that might confer resistance to enzalutamide, we performed a reporter-based mutagenesis screen and identified a novel mutation, F876L, which converted enzalutamide into an AR agonist. Ectopic expression of AR F876L rescued the growth inhibition of enzalutamide treatment. Molecular dynamics simulations performed on antiandrogen-AR complexes suggested a mechanism by which the F876L substitution alleviates antagonism through repositioning of the coactivator recruiting helix 12. This model then provided the rationale for a focused chemical screen which, based on existing antiandrogen scaffolds, identified three novel compounds that effectively antagonized AR F876L (and AR WT) to suppress the growth of prostate cancer cells resistant to enzalutamide. DOI:http://dx.doi.org/10.7554/eLife.00499.001.
authors.affiliation: Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences , Memorial Sloan-Kettering Cancer Center , New York , United States ; Human Oncology and Pathogenesis Program , Memorial Sloan-Kettering Cancer Center , New York , United States.
authors.forename: Minna D
authors.initials: MD
authors.lastname: Balbas
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Evans
authors.forename: David J
authors.initials: DJ
authors.lastname: Hosfield
authors.forename: John
authors.initials: J
authors.lastname: Wongvipat
authors.forename: Vivek K
authors.initials: VK
authors.lastname: Arora
authors.forename: Philip A
authors.initials: PA
authors.lastname: Watson
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Greene
authors.forename: Yang
authors.initials: Y
authors.lastname: Shen
authors.forename: Charles L
authors.initials: CL
authors.lastname: Sawyers
mesh_terms: D000726:Androgen Antagonists / Q000737:chemistry / Q000627:therapeutic use*; D002460:Cell Line; D015195:Drug Design; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D008297:Male; D056004:Molecular Dynamics Simulation; D009154:Mutation; D011471:Prostatic Neoplasms / Q000188:drug therapy
chemical_list: D000726:Androgen Antagonists
keywords: Human; Mouse; androgen receptor; drug resistance; prostate cancer