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Review
. 2017 Feb;19(2):13.
doi: 10.1007/s11912-017-0568-7.

Mechanisms of Therapeutic Resistance in Prostate Cancer

Mary Nakazawa  1 , Channing Paller  2 , Natasha Kyprianou  3
Affiliations
Review

Mechanisms of Therapeutic Resistance in Prostate Cancer

Mary Nakazawa et al. Curr Oncol Rep. 2017 Feb.

Abstract

Prostate cancer is the second leading cause of cancer deaths in the USA. The challenge in managing castration-resistant prostate cancer (CRPC) stems not from the lack of therapeutic options but from the limited duration of clinical and survival benefit offered by treatments in this setting due to primary and acquired resistance. The remarkable molecular heterogeneity and tumor adaptability in advanced prostate cancer necessitate optimization of such treatment strategies. While the future of CRPC management will involve newer targeted therapies in deliberately biomarker-selected patients, interventions using current approaches may exhibit improved clinical benefit if employed in the context of optimal sequencing and combinations. This review outlines our current understanding of mechanisms of therapeutic resistance in progression to and after the development of castration resistance, highlighting targetable and reversible mechanisms of resistance.

Keywords: Castration-resistant prostate cancer; Prostate cancer; Therapeutic resistance.

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Conflict of interest statement

Conflict of Interest Mary Nakazawa, Channing Paller, and Natasha Kyprianou declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Major mechanisms of therapeutic resistance to androgen axis-targeting therapies in prostate cancer. A AR gene and mRNA amplifications to increase ligand sensitivity. B Utilization of nonandrogen ligands such as estradiol and glucocorticoids. C AR activation via alternative survival signaling pathways including PI3K/AKT, NF-κB, and RTKs. D AR coactivators can enhance AR sensitivity to various alternative ligands. E Utilization of alternative ligand synthesis pathways for conversion of adrenal androgen precursors. F Activation of TGF-β signaling pathway in EMT-to-MET interconversions. G Overexpression of prosurvival molecules such as Bcl-2 contributing to evasion of apoptosis activation. H AR splice variants with ligand-independent activation promote AR transcriptional programs in the absence of ligand
See this image and copyright information in PMC

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MeSH terms