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Updated: Jan 29, 2026

Residue-specific Incorporation of Noncanonical Amino Acids into Model Proteins Using an Escherichia coli Cell-free Transcription-translation System
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Coactivator networks orchestrating noncanonical AR programs in enzalutamide-resistant CRPC

Ephraim J Gardner1,2, Sasikumar Ponnusamy1, Remi Adelaiye-Ogala1,2,3,4

  • 1Division of Hematology and Oncology, Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, United States.

Frontiers in Oncology
|January 28, 2026
PubMed

Insights

Resistance to androgen receptor (AR)-targeted therapies in prostate cancer can be overcome. New coactivators drive noncanonical AR signaling, enabling cancer cells to evade treatment. Targeting these coactivators offers a novel therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Castration-resistant prostate cancer (CRPC) poses significant treatment challenges.
  • Resistance to androgen receptor (AR)-targeted therapies is a major clinical hurdle.
  • Enzalutamide resistance involves epigenomic reprogramming of AR cistrome towards noncanonical gene networks.

Purpose of the Study:

  • To investigate the mechanisms of Enzalutamide resistance in CRPC.
  • To identify novel coactivators mediating AR-dependent therapeutic evasion.
  • To explore therapeutic strategies targeting noncanonical AR signaling.

Main Methods:

  • Analysis of AR cistrome reprogramming in CRPC.
  • Identification and characterization of novel AR coactivators (CXXC5, TET2, EZH2).
  • Pharmacologic disruption of identified coactivators in preclinical models.

Main Results:

  • AR resistance is driven by epigenomic reprogramming and noncanonical AR transcriptional programs.
  • CXXC5, TET2, and EZH2 cooperate with AR to promote lineage plasticity and therapeutic evasion.
  • Pharmacologic inhibition of these coactivators abrogates noncanonical AR activity and suppresses tumor growth.

Conclusions:

  • Noncanonical AR coactivators represent a novel therapeutic target for overcoming Enzalutamide resistance in CRPC.
  • Targeting these coactivators offers a new paradigm for treating advanced prostate cancer.
  • Further research using single-cell and epigenomic profiling will elucidate AR cistrome remodeling dynamics.
Keywords:
AR cistromeadvanced prostate cancerandrogen receptorcanonical and noncanonical AR cistromeenzalutamide resistancelineage plasticitynoncanonical AR coactivatortherapeutic strategies

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