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Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
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Mechanisms and Therapeutic Strategies to Overcome Enzalutamide Resistance in Advanced Prostate Cancer

Xinyi Wang1, Zhiguo Li1, Xiaoqi Liu1,2

  • 1Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky 40536, USA.

Serican Journal of Medicine
|June 22, 2026
PubMed

Insights

Resistance to enzalutamide, a prostate cancer drug, is common. This review explores resistance mechanisms and new strategies like combination therapies and personalized medicine to improve treatment for metastatic castration-resistant prostate cancer (mCRPC).

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Enzalutamide improves survival in metastatic castration-resistant prostate cancer (mCRPC).
  • Therapeutic resistance to enzalutamide is a significant clinical challenge, limiting long-term patient benefit.
  • Understanding resistance mechanisms is crucial for developing effective treatment strategies.

Purpose of the Study:

  • To comprehensively review the mechanisms of enzalutamide resistance in mCRPC.
  • To explore emerging therapeutic strategies to overcome this resistance.
  • To highlight the role of biomarkers and drug repurposing in personalized medicine for resistant prostate cancer.

Main Methods:

  • Literature review of preclinical and clinical studies on enzalutamide resistance.
  • Analysis of genetic alterations, signaling pathway activation, and tumor microenvironment factors contributing to resistance.
  • Evaluation of novel therapeutic approaches, including combination therapies and next-generation inhibitors.

Main Results:

  • Enzalutamide resistance involves AR alterations (amplification, mutations, splice variants like AR-V7), bypass signaling (glucocorticoid receptor, PI3K/Akt/mTOR, Wnt), and tumor microenvironment factors.
  • Lineage plasticity and neuroendocrine differentiation also contribute to resistance via immune evasion and epigenetic changes.
  • Combination therapies (e.g., with PARP inhibitors, epigenetic modulators) and next-generation AR inhibitors show promise.

Conclusions:

  • Multifaceted mechanisms drive enzalutamide resistance in mCRPC.
  • Targeting these diverse pathways and leveraging personalized medicine approaches are key to overcoming resistance.
  • Future strategies may involve drug repurposing and combination treatments for more durable responses in mCRPC patients.
Keywords:
Castration resistanceEnzalutamide resistanceprostate cancer

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