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Published on: June 9, 2017
The interconnection between androgen receptor and DNA damage response pathways in prostate cancer
Mallory Sands1, Samuel Adams1, Jihaeng Lee1
1Department of Biological Sciences, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN, USA.
Abstract:
The androgen receptor (AR) plays a critical role in the development and progression of prostate cancer by regulating key cellular processes such as cell proliferation and apoptosis. Although traditional AR-targeted therapies have shown initial success, acquired resistance remains a significant clinical challenge, often driven by AR alterations and somatic gene mutations associated with homologous recombination deficiency (HRD). Approximately 20% of advanced prostate cancer cases exhibit HRD, resulting in substantial genomic instability and complicating treatment. Fortunately, Food and Drug Administration-approved poly(ADP-ribose) polymerase inhibitors, including olaparib and rucaparib, exploit synthetic lethality to target prostate cancer with HRD, and additional drugs targeting DNA damage response (DDR) proteins are under development. Emerging evidence suggests that AR activity enhances DDR gene expression, with multiple DDR proteins localized near androgen-regulated regions, highlighting a close interaction between AR and DDR pathways. Consequently, recent preclinical and clinical studies have investigated combining AR-targeted therapies with treatments that induce DNA damage, such as radiation therapy, or inhibit DNA repair mechanisms. This review discusses AR's role in cellular processes, the interplay between AR and DDR, and recent advances in prostate cancer treatment strategies.
Insights
Androgen receptor (AR) signaling drives prostate cancer, but resistance emerges. Targeting AR and DNA damage response (DDR) pathways offers new hope for advanced prostate cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The androgen receptor (AR) is crucial in prostate cancer development and progression.
- Acquired resistance to AR-targeted therapies is a major clinical hurdle, often linked to AR alterations and homologous recombination deficiency (HRD).
- HRD occurs in about 20% of advanced prostate cancer cases, leading to genomic instability.
Purpose of the Study:
- To review the role of AR in cellular processes.
- To explore the interplay between AR and DNA damage response (DDR) pathways.
- To discuss recent advances in prostate cancer treatment strategies combining AR-targeted therapies with DDR-targeting agents.
Main Methods:
- Literature review of preclinical and clinical studies.
- Analysis of the interaction between AR signaling and DDR pathways.
- Examination of emerging treatment strategies for advanced prostate cancer.
Main Results:
- AR activity influences DDR gene expression, with DDR proteins often found near AR-regulated regions.
- Poly(ADP-ribose) polymerase (PARP) inhibitors like olaparib and rucaparib are FDA-approved for HRD-positive prostate cancer.
- Combination therapies involving AR-targeted agents and DNA-damaging or DNA-repair inhibiting treatments are under investigation.
Conclusions:
- The close interaction between AR and DDR pathways presents a promising therapeutic target.
- Combining AR-targeted therapies with DNA damage or repair inhibition strategies may overcome treatment resistance in advanced prostate cancer.
- Further research into these combination therapies is warranted to improve patient outcomes.
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