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Prostate Organoid Cultures as Tools to Translate Genotypes and Mutational Profiles to Pharmacological Responses
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Resistance to second generation antiandrogens in prostate cancer: pathways and mechanisms

Shiv Verma1,2, Kumari Sunita Prajapati3, Prem Prakash Kushwaha3

  • 1Department of Urology, Case Western Reserve University, Cleveland, OH 44106, USA.

Cancer Drug Resistance (Alhambra, Calif.)
|May 18, 2022
PubMed

Insights

Second-generation antiandrogens improve survival for advanced prostate cancer, but resistance develops. Understanding androgen receptor (AR) signaling resistance mechanisms is key to developing new treatments for castration-resistant prostate cancer (CRPC).

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Androgen deprivation therapy (ADT) targeting androgen receptor (AR) signaling is a primary treatment for advanced prostate cancer.
  • Second-generation antiandrogens like abiraterone acetate and enzalutamide have extended patient survival.
  • However, most patients eventually develop resistance, progressing to castration-resistant prostate cancer (CRPC).

Purpose of the Study:

  • To review the major mechanisms of acquired resistance to second-generation antiandrogens in prostate cancer.
  • To discuss both androgen receptor (AR)-dependent and AR-independent resistance pathways.
  • To highlight other resistance mechanisms contributing to CRPC emergence.

Main Methods:

  • Literature review focusing on mechanisms of resistance to antiandrogen therapies.
  • Analysis of studies detailing AR-dependent and AR-independent resistance pathways.
  • Synthesis of current knowledge on molecular alterations driving CRPC.

Main Results:

  • Resistance to antiandrogens involves complex mechanisms, including AR mutations, alternative splicing, and oncogenic protein amplification.
  • Both AR-dependent (e.g., AR amplification, mutations) and AR-independent (e.g., bypass signaling pathways) mechanisms contribute to treatment failure.
  • These alterations lead to the dysregulation of various signaling pathways, ultimately causing CRPC.

Conclusions:

  • Understanding the multifaceted mechanisms of acquired resistance is crucial for overcoming treatment limitations.
  • Further research into these resistance pathways will facilitate the development of more effective therapies for advanced prostate cancer.
  • Targeting novel pathways and combination strategies may overcome resistance to current antiandrogen treatments.
Keywords:
Prostate cancerandrogen receptorcastration resistance prostate cancersecond-generation antiandrogens

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