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Androgen receptor antagonism drives cytochrome P450 17A1 inhibitor efficacy in prostate cancer.
Norris, John D; Ellison, Stephanie J; Baker, Jennifer G; Stagg, David B; Wardell, Suzanne E; Park, Sunghee; Alley, Holly M; Baldi, Robert M; Yllanes, Alexander; Andreano, Kaitlyn J; Stice, James P; Lawrence, Scott A; Eisner, Joel R; Price, Douglas K; Moore, William R; Figg, William D; McDonnell, Donald P.
Afiliação
  • Norris JD; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA.
  • Ellison SJ; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA.
  • Baker JG; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA.
  • Stagg DB; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA.
  • Wardell SE; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA.
  • Park S; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA.
  • Alley HM; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA.
  • Baldi RM; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA.
  • Yllanes A; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA.
  • Andreano KJ; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA.
  • Stice JP; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA.
  • Lawrence SA; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA.
  • Eisner JR; Innocrin Pharmaceuticals Inc., Durham, North Carolina, USA.
  • Price DK; Genitourinary Malignancies Branch, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA.
  • Moore WR; Innocrin Pharmaceuticals Inc., Durham, North Carolina, USA.
  • Figg WD; Genitourinary Malignancies Branch, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA.
  • McDonnell DP; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA.
J Clin Invest ; 127(6): 2326-2338, 2017 Jun 01.
Article em En | MEDLINE | ID: mdl-28463227
The clinical utility of inhibiting cytochrome P450 17A1 (CYP17), a cytochrome p450 enzyme that is required for the production of androgens, has been exemplified by the approval of abiraterone for the treatment of castration-resistant prostate cancer (CRPC). Recently, however, it has been reported that CYP17 inhibitors can interact directly with the androgen receptor (AR). A phase I study recently reported that seviteronel, a CYP17 lyase-selective inhibitor, ædemonstrated a sustained reduction in prostate-specific antigen in a patient with CRPC, and another study showed seviteronel's direct effects on AR function. This suggested that seviteronel may have therapeutically relevant activities in addition to its ability to inhibit androgen production. Here, we have demonstrated that CYP17 inhibitors, with the exception of orteronel, can function as competitive AR antagonists. Conformational profiling revealed that the CYP17 inhibitor-bound AR adopted a conformation that resembled the unliganded AR (apo-AR), precluding nuclear localization and DNA binding. Further, we observed that seviteronel and abiraterone inhibited the growth of tumor xenografts expressing the clinically relevant mutation AR-F876L and that this activity could be attributed entirely to competitive AR antagonism. The results of this study suggest that the ability of CYP17 inhibitors to directly antagonize the AR may contribute to their clinical efficacy in CRPC.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Esteroide 17-alfa-Hidroxilase / Antineoplásicos Hormonais / Antagonistas de Receptores de Andrógenos / Neoplasias de Próstata Resistentes à Castração Limite: Animals / Humans / Male Idioma: En Revista: J Clin Invest Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Esteroide 17-alfa-Hidroxilase / Antineoplásicos Hormonais / Antagonistas de Receptores de Andrógenos / Neoplasias de Próstata Resistentes à Castração Limite: Animals / Humans / Male Idioma: En Revista: J Clin Invest Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Estados Unidos