title: CDK4/6 Therapeutic Intervention and Viable Alternative to Taxanes in CRPC.
abstract: Resistance to second-generation androgen receptor (AR) antagonists and CYP17 inhibitors in patients with castration-resistant prostate cancer (CRPC) develops rapidly through reactivation of the androgen signaling axis and has been attributed to AR overexpression, production of constitutively active AR splice variants, or the selection for AR mutants with altered ligand-binding specificity. It has been established that androgens induce cell-cycle progression, in part, through upregulation of cyclin D1 (CCND1) expression and subsequent activation of cyclin-dependent kinases 4 and 6 (CDK4/6). Thus, the efficacy of the newly described CDK4/6 inhibitors (G1T28 and G1T38), docetaxel and enzalutamide, was evaluated as single agents in clinically relevantin vitroandin vivomodels of hormone-sensitive and treatment-resistant prostate cancer. CDK4/6 inhibition (CDK4/6i) was as effective as docetaxel in animal models of treatment-resistant CRPC but exhibited significantly less toxicity. Thein vivoeffects were durable and importantly were observed in prostate cancer cells expressing wild-type AR, AR mutants, and those that have lost AR expression. CDK4/6i was also effective in prostate tumor models expressing the AR-V7 variant or the AR F876L mutation, both of which are associated with treatment resistance. Furthermore, CDK4/6i was effective in prostate cancer models where AR expression was lost. It is concluded that CDK4/6 inhibitors are a viable alternative to taxanes as therapeutic interventions in endocrine therapy-refractory CRPC.Implications:The preclinical efficacy of CDK4/6 monotherapy observed here suggests the need for near-term clinical studies of these agents in advanced prostate cancer.Mol Cancer Res; 15(6); 660-9. ©2017 AACR.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina.
authors.forename: James P
authors.initials: JP
authors.lastname: Stice
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina.
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Wardell
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina.
authors.forename: John D
authors.initials: JD
authors.lastname: Norris
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina.
authors.forename: Alexander P
authors.initials: AP
authors.lastname: Yllanes
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina.
authors.forename: Holly M
authors.initials: HM
authors.lastname: Alley
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina.
authors.forename: Victoria O
authors.initials: VO
authors.lastname: Haney
authors.affiliation: G1 Therapeutics, Inc., Research Triangle Park, North Carolina.
authors.forename: Hannah S
authors.initials: HS
authors.lastname: White
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina.
authors.forename: Rachid
authors.initials: R
authors.lastname: Safi
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Winter
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina.
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Cocce
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina.
authors.forename: Rigel J
authors.initials: RJ
authors.lastname: Kishton
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Lawrence
authors.affiliation: G1 Therapeutics, Inc., Research Triangle Park, North Carolina.
authors.forename: Jay C
authors.initials: JC
authors.lastname: Strum
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina. donald.mcdonnell@duke.edu.
authors.forename: Donald P
authors.initials: DP
authors.lastname: McDonnell
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors*; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D008297:Male; D008819:Mice, Nude; D058990:Molecular Targeted Therapy / Q000379:methods; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D043823:Taxoids / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D043823:Taxoids; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6