CDK4/6 Therapeutic Intervention and Viable Alternative to Taxanes in CRPC

• Published in: Molecular cancer research Vol. 15; no. 6; pp. 660 - 669
• Main Authors: Stice, James P, Wardell, Suzanne E, Norris, John D, Yllanes, Alexander P, Alley, Holly M, Haney, Victoria O, White, Hannah S, Safi, Rachid, Winter, Peter S, Cocce, Kimberly J, Kishton, Rigel J, Lawrence, Scott A, Strum, Jay C, McDonnell, Donald P
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 01.06.2017
• Subjects: Activation; Alternative splicing; Androgen receptors; Androgens; Animal models; Animals; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Biocompatibility; Cancer; Castration; Cell Line, Tumor; Cyclin D1; Cyclin-dependent kinase 4; Cyclin-Dependent Kinase 4 - antagonists & inhibitors; Cyclin-Dependent Kinase 6 - antagonists & inhibitors; Drug Resistance, Neoplasm - drug effects; Endocrine therapy; Humans; Inhibitors; Kinases; Male; Mice, Nude; Molecular Targeted Therapy - methods; Mutants; Prostate cancer; Prostatic Neoplasms, Castration-Resistant - drug therapy; Prostatic Neoplasms, Castration-Resistant - pathology; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - pharmacology; Signaling; Taxanes; Taxoids - pharmacology; Therapeutic applications; Toxicity; Xenograft Model Antitumor Assays
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.mcr-17-0028

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 relevant and models 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. The effects 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. The preclinical efficacy of CDK4/6 monotherapy observed here suggests the need for near-term clinical studies of these agents in advanced prostate cancer. .