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Published on: October 24, 2019
Overcoming drug resistance in castrate-resistant prostate cancer: current mechanisms and emerging therapeutic
Adam Khorasanchi1, Feng Hong2,3, Yuanquan Yang2,3
1Division of Hospital Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
Abstract:
Metastatic castration-resistant prostate cancer (mCRPC) is driven by a complex network of resistance mechanisms against standard-of-care therapies, resulting in poor long-term outcomes. This review offers a uniquely comprehensive and integrative perspective on these resistance pathways, systematically examining both androgen receptor (AR)-dependent factors (including AR overexpression, point mutations, glucocorticoid receptor signaling, splice variants, post-translational modifications, altered coregulators, and intratumoral hormone biosynthesis) and AR-independent pathways (such as neuroendocrine differentiation, lineage plasticity, and alternative growth factor signaling). We also highlight resistance mechanisms influencing immunotherapy, chemotherapy, radiopharmaceutical therapy and targeted therapy. By synthesizing emerging insights across these domains, this review not only clarifies the underlying biology of mCRPC resistance but also identifies key leverage points for more effective interventions. Building on this foundation, we propose a forward-looking framework for overcoming mCRPC drug resistance, emphasizing the importance of biomarker-guided patient selection, combination strategies that simultaneously target multiple resistance mechanisms, and novel therapies under investigation. These recommendations are intended to guide future clinical trial designs and research priorities that move beyond incremental improvements. Ultimately, this comprehensive synthesis aims to serve as a resource for clinicians and researchers to accelerate the development of durable, precision-based treatment strategies in mCRPC.
Insights
Metastatic castration-resistant prostate cancer (mCRPC) involves complex resistance mechanisms. This review integrates AR-dependent and independent pathways to guide precision therapies and combination strategies for improved patient outcomes.
Area of Science:
- Oncology
- Cancer Biology
- Translational Medicine
Background:
- Metastatic castration-resistant prostate cancer (mCRPC) presents significant therapeutic challenges due to diverse resistance mechanisms.
- Standard-of-care treatments for mCRPC are often undermined by complex biological adaptations within cancer cells.
- Poor long-term outcomes in mCRPC underscore the urgent need to understand and overcome treatment resistance.
Purpose of the Study:
- To provide a comprehensive review of androgen receptor (AR)-dependent and AR-independent resistance mechanisms in mCRPC.
- To synthesize current knowledge on resistance to various mCRPC therapies, including immunotherapy, chemotherapy, and targeted agents.
- To identify key leverage points and propose a framework for developing more effective, precision-based interventions against mCRPC drug resistance.
Main Methods:
- Systematic review and integration of existing literature on mCRPC resistance pathways.
- Analysis of AR-dependent factors such as AR overexpression, mutations, splice variants, and signaling.
- Examination of AR-independent pathways including neuroendocrine differentiation and lineage plasticity.
Main Results:
- Identified a complex network of AR-dependent and AR-independent resistance mechanisms contributing to mCRPC progression.
- Highlighted how these resistance pathways impact the efficacy of immunotherapy, chemotherapy, and radiopharmaceutical therapy.
- Synthesized emerging insights to clarify the underlying biology of mCRPC resistance.
Conclusions:
- Understanding the multifaceted nature of mCRPC resistance is crucial for developing durable treatment strategies.
- Biomarker-guided patient selection and combination therapies targeting multiple resistance mechanisms are essential.
- Future research and clinical trials should focus on novel therapies and integrated approaches to overcome mCRPC drug resistance.
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07:25A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
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08:46Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
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