Molecular Mechanisms of Treatment Resistance in Prostate Cancer

A Special Issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: 15 September 2026 | Viewed by 2765

Editor


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Guest Editor
Department of Urologic Sciences, The University of British Columbia, Vancouver, BC V6T 2B5, Canada
Interests: androgen receptor; prostate cancer; treatment resistance; cell signaling pathways; SEMA3C
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Special Issue Information

Dear Colleagues,

Metastatic castration-resistant prostate cancer (mCRPC) remains a difficult clinical challenge, driven by tumor heterogeneity, diverse progression pathways and complex resistance mechanisms. This Special Issue, “Molecular Mechanisms of Treatment Resistance in Prostate Cancer”, seeks original research and comprehensive reviews on the following topics:

  • Precision systemic therapies, including approaches against traditionally “undruggable” targets.
  • Genetic and epigenetic alterations driving disease progression.
  • The role of cellular plasticity and lineage reprogramming.
  • Tumor microenvironment signaling and therapeutic modulation.
  • Mechanisms of resistance to current androgen‐targeted and cytotoxic treatments.
  • Immunotherapeutic strategies and combination therapies.
  • Targeted radiotherapy, including radioligand approaches.
  • Novel biomarkers for patient stratification and treatment response monitoring.

The aim of this Special Issue is to deepen our understanding of the complex mechanisms driving mCRPC and to showcase innovative therapeutic avenues that can improve patient survival and quality of life.

Dr. Christopher J. Ong
Guest Editor

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Keywords

  • metastatic castration-resistant prostate cancer (mCRPC)
  • molecular mechanisms
  • novel treatment strategies
  • systemic precision treatments
  • epigenetics
  • cellular plasticity
  • tumor microenvironment signaling
  • therapeutic resistance

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Published Papers (1 paper)

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Review

24 pages, 1297 KB  
Review
PARP Inhibition in Prostate Cancer: Current Status, Resistance Mechanisms, and Clinical Challenges
by Takashi Matsuoka, Shusuke Akamatsu, Christopher J. Ong, Martin E. Gleave and Yuzhuo Wang
Cells 2026, 15(7), 588; https://doi.org/10.3390/cells15070588 - 26 Mar 2026
Viewed by 2271
Abstract
Poly(ADP-ribose) polymerase inhibitors (PARPi) have reshaped therapy for advanced prostate cancer, yet durable benefit remains concentrated in BRCA1/2-altered tumors, especially BRCA2, and most responders eventually relapse. Here, we frame PARPi response and resistance through a unifying model in which DNA damage response (DDR) [...] Read more.
Poly(ADP-ribose) polymerase inhibitors (PARPi) have reshaped therapy for advanced prostate cancer, yet durable benefit remains concentrated in BRCA1/2-altered tumors, especially BRCA2, and most responders eventually relapse. Here, we frame PARPi response and resistance through a unifying model in which DNA damage response (DDR) rewiring (e.g., homologous recombination repair (HRR) restoration, fork protection, checkpoint tolerance, and altered drug handling) converges with treatment-induced dormancy and quiescent therapy-tolerant residual states that sustain minimal residual disease (MRD) under androgen receptor pathway inhibition (ARPI) and PARP blockade. We synthesize clinical and translational evidence for PARPi monotherapy and PARPi-based combinations across disease states. In first-line metastatic castration-resistant prostate cancer (mCRPC), PARPi plus ARPI consistently prolongs radiographic progression-free survival, with the greatest benefit in HRR-altered tumors, and emerging overall-survival signals in selected subgroups. In later-line settings, monotherapy activity is most robust in BRCA2-mutated disease, whereas non-BRCA HRR alterations show heterogeneous and often modest responses, underscoring the need for biomarkers beyond gene panels. We also discuss combination strategies with DDR-targeting agents, radioligand therapies, and immunotherapy, and summarize ongoing phase III programs in metastatic castration-sensitive prostate cancer (mCSPC). Finally, we outline practical considerations for biomarker-informed patient selection, monitoring, sequencing, and toxicity management, with particular emphasis on intercepting MRD and resistance evolution. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Treatment Resistance in Prostate Cancer)
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