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Updated: Aug 31, 2025

Prostate Organoid Cultures as Tools to Translate Genotypes and Mutational Profiles to Pharmacological Responses
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Phenotypic Plasticity - Alternate Transcriptional Programs Driving Treatment Resistant Prostate Cancer

Jagpreet Singh Nanda1, Praveen Koganti1, Graziela Perri1

  • 1Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048; Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA 90048.

Critical Reviews in Oncogenesis
|August 22, 2022
PubMed

Insights

Androgen deprivation therapy resistance in prostate cancer can occur through epigenetic plasticity, not just AR signaling. Targeting the epigenome offers a new strategy for durable treatment responses in castration-resistant prostate cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Androgen deprivation therapy (ADT) improves survival for prostate cancer patients but is not curative.
  • Prostate cancer frequently progresses to castration-resistant prostate cancer (CRPC).
  • A subset of CRPC develops resistance through mechanisms independent of androgen receptor (AR) signaling.

Purpose of the Study:

  • To discuss epigenetic mechanisms driving phenotypic plasticity in ADT-resistant prostate cancer.
  • To explore the potential of targeting the epigenome for novel therapeutic strategies.
  • To highlight combination strategies involving epigenetic therapy for durable responses.

Main Methods:

  • Review of current literature on epigenetic mechanisms in prostate cancer.
  • Analysis of phenotypic plasticity and gene expression signatures in CRPC.
  • Discussion of therapeutic targets within the epigenome.

Main Results:

  • Phenotypic plasticity, including epithelial-mesenchymal transition, is activated in a quarter of progressing prostate cancers.
  • Developmental and stemness gene signatures are activated in these resistant tumors.
  • Epigenetic alterations mediate these plastic changes, offering potential therapeutic vulnerabilities.

Conclusions:

  • Prostate cancer can acquire ADT resistance via epigenetic mechanisms driving phenotypic plasticity.
  • Targeting the epigenome represents a promising avenue for treating CRPC.
  • Combination epigenetic therapies may provide durable responses for patients with advanced prostate cancer.

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