Resistance emerges to second-generation antiandrogens in prostate cancer

Area of Science:

• Oncology
• Molecular Biology
• Endocrinology

Background:

• Prostate cancer treatment often involves androgen deprivation therapy.
• Second-generation antiandrogen drugs, such as enzalutamide and ARN-509, are critical for managing advanced prostate cancer.
• Resistance to these therapies can develop, limiting long-term patient outcomes.

Purpose of the Study:

• To investigate the molecular mechanisms underlying resistance to second-generation antiandrogen drugs in prostate cancer.
• To identify specific mutations in the androgen receptor (AR) that confer resistance.
• To understand how these mutations alter AR function and impact treatment efficacy.

Main Methods:

• Prostate cancer cell lines were chronically exposed to enzalutamide and ARN-509.
• Genetic sequencing was performed to identify mutations in the androgen receptor (AR).
• Functional assays were used to assess the agonist/antagonist activity of wild-type and mutant AR.

Main Results:

• A specific mutation, AR(F876L), was identified in prostate cancer cells resistant to enzalutamide and ARN-509.
• The AR(F876L) mutation promotes a functional switch of the androgen receptor from an antagonist to an agonist.
• This switch in AR function drives continued cancer cell proliferation despite antiandrogen treatment.

Conclusions:

• The emergence of the AR(F876L) mutation is a key mechanism of resistance to enzalutamide and ARN-509 in prostate cancer.
• This mutation converts antiandrogen drugs into agonists, paradoxically stimulating cancer growth.
• Targeting or overcoming this specific AR mutation may be necessary for improving long-term treatment strategies for advanced prostate cancer.