An F876L mutation in androgen receptor confers genetic and phenotypic resistance to MDV3100 (enzalutamide).

Abstract

UNLABELLED:

Castration-resistant prostate cancer (CRPC) is the most aggressive, incurable form of prostate cancer. MDV3100 (enzalutamide), an antagonist of the androgen receptor (AR), was approved for clinical use in men with metastatic CRPC. Although this compound showed clinical efficacy, many initial responders later developed resistance. To uncover relevant resistant mechanisms, we developed a model of spontaneous resistance to MDV3100 in LNCaP prostate cancer cells. Detailed characterization revealed that emergence of an F876L mutation in AR correlated with blunted AR response to MDV3100 and sustained proliferation during treatment. Functional studies confirmed that AR(F876L) confers an antagonist-to-agonist switch that drives phenotypic resistance. Finally, treatment with distinct antiandrogens or cyclin-dependent kinase (CDK)4/6 inhibitors effectively antagonized AR(F876L) function. Together, these findings suggest that emergence of F876L may (i) serve as a novel biomarker for prediction of drug sensitivity, (ii) predict a "withdrawal" response to MDV3100, and (iii) be suitably targeted with other antiandrogens or CDK4/6 inhibitors.

SIGNIFICANCE:

We uncovered an F876L agonist-switch mutation in AR that confers genetic and phenotypic resistance to the antiandrogen drug MDV3100. On the basis of this fi nding, we propose new therapeutic strategies to treat patients with prostate cancer presenting with this AR mutation.

• Authors: Manav Korpal, Joshua M Korn, Xueliang Gao, Daniel P Rakiec, David A Ruddy, Shivang Doshi, Jing Yuan, Steve G Kovats, Sunkyu Kim, Vesselina G Cooke, John E Monahan, Frank Stegmeier, Thomas M Roberts, William R Sellers, Wenlai Zhou, Ping Zhu
• Journal: Cancer discovery (Cancer Discov) Vol. 3 Issue 9 Pg. 1030-43 (Sep 2013) ISSN: 2159-8290 [Electronic] United States
• PMID: 23842682 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2013 AACR.

Chemical References

• AR protein, human
• Androgen Antagonists
• Androgen Receptor Antagonists
• Benzamides
• Nitriles
• Receptors, Androgen
• Phenylthiohydantoin
• enzalutamide
• CDK4 protein, human
• CDK6 protein, human
• Cyclin-Dependent Kinase 4
• Cyclin-Dependent Kinase 6

Topics

• Androgen Antagonists (pharmacology)
• Androgen Receptor Antagonists (pharmacology)
• Base Sequence
• Benzamides
• Cell Line, Tumor
• Cyclin-Dependent Kinase 4 (antagonists & inhibitors)
• Cyclin-Dependent Kinase 6 (antagonists & inhibitors)
• Drug Resistance, Neoplasm (genetics)
• Humans
• Male
• Mutation
• Nitriles
• Phenylthiohydantoin (analogs & derivatives, pharmacology)
• Prostatic Neoplasms, Castration-Resistant (drug therapy)
• Receptors, Androgen (genetics)
• Sequence Analysis, DNA