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Updated: May 10, 2026

Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
08:46

Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms

Published on: December 9, 2015

A clinically relevant androgen receptor mutation confers resistance to second-generation antiandrogens enzalutamide

James D Joseph1, Nhin Lu, Jing Qian

  • 1Aragon Pharmaceuticals, Inc., San Diego, California.

Cancer Discovery
|June 20, 2013
PubMed
Abstract

Insights

A specific mutation (F876L) in the androgen receptor (AR) causes resistance to prostate cancer drugs like enzalutamide. This AR F876L mutation is found in patients, suggesting new drug targets for advanced prostate cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Second-generation antiandrogens, such as enzalutamide and ARN-509, show significant clinical activity in prostate cancer treatment.
  • Acquired resistance to these antiandrogens is a major clinical challenge, limiting long-term treatment efficacy.

Purpose of the Study:

  • To investigate the molecular mechanisms driving acquired resistance to enzalutamide and ARN-509 in prostate cancer.
  • To identify specific genetic alterations in the androgen receptor (AR) associated with antiandrogen resistance.

Main Methods:

  • Development and characterization of cell lines resistant to ARN-509 and enzalutamide.
  • In vitro and in vivo modeling of castration-resistant prostate cancer (CRPC) using engineered cell lines.
  • Detection of AR mutations in plasma DNA from patients with progressive CRPC.

Main Results:

  • A subset of resistant cell lines exhibited agonist activity of AR due to a missense mutation, F876L, in the ligand-binding domain.
  • The AR F876L mutation was sufficient to confer resistance to both enzalutamide and ARN-509 in preclinical models.
  • The AR F876L mutant was detected in circulating plasma DNA of patients with progressive CRPC receiving ARN-509 treatment.

Conclusions:

  • The F876L mutation in the androgen receptor is a clinically relevant mechanism for acquired resistance to second-generation antiandrogens.
  • Targeting the AR F876L mutant with next-generation antiandrogens presents a potential therapeutic strategy.
  • These findings support the development of companion diagnostics for guiding treatment decisions in advanced prostate cancer.

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