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
Summary
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.
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