Genomic Resistance Patterns to Second-Generation Androgen Blockade in Paired Tumor Biopsies of Metastatic Castration-Resistant Prostate Cancer.

Abstract

PURPOSE:

Patients with castration-resistant prostate cancer (CRPC) receive second-generation androgen-deprivation therapy, but frequently experience relapse or do not respond. Understanding the genetic mechanisms of resistance will help to identify strategies and biomarkers that are essential for the next line of therapy.

PATIENTS AND METHODS:

We analyzed whole exomes of patient-matched pre- and post-treatment tumors from patients with CRPC. These patients had received the secondary androgen-deprivation therapy agent, abiraterone, which suppresses androgens to below castration levels, or enzalutamide, which competitively inhibits the key androgen signaling effector, androgen receptor.

RESULTS:

We observed that abiraterone-resistant tumors harbored alterations in AR and MYC, whereas enzalutamide-resistant tumors gained alterations in cell-cycle pathway genes, such as mutation in cyclin-dependent kinase N2A (CDKN2A) or amplification of CDK6. Experimentally, overexpressing cell-cycle kinases promoted enzalutamide resistance in androgen-sensitive LnCAP cells that was mitigated via CDK4/6 blockade-palbociclib and ribociclib.

CONCLUSION:

CDK4/6-mediated resistance observed in preclinical experiments suggests that CDK4/6 amplifications may sufficiently promote enzalutamide resistance in CRPC, and that these patients may respond to palbociclib or ribociclib. The overall observations suggest that, in genomically selected advanced CRPC, clinical strategies against abiraterone- or enzalutamide-resistant tumors may require treatment strategies that are tailored to the resistance mechanisms that are specific to those patient subpopulations.

• Authors: G Celine Han, Justin Hwang, Stephanie A M Wankowicz, Zhenwei Zhang, David Liu, Carrie Cibulskis, Glenn C Gaviola, Varand Ghazikhanian, Rana R McKay, Glenn J Bubley, Scott L Carter, Steven P Balk, William C Hahn, Mary-Ellen Taplin, Eliezer M Van Allen
• Journal: JCO precision oncology (JCO Precis Oncol) Vol. 1 ( 2017) ISSN: 2473-4284 [Electronic] United States
• PMID: 32913968 (Publication Type: Journal Article)
• Copyright: © 2017 by American Society of Clinical Oncology.