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Molecular events in neuroendocrine prostate cancer development

Abstract

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer. NEPC arises de novo only rarely; the disease predominantly develops from adenocarcinoma in response to drug-induced androgen receptor signalling inhibition, although the mechanisms behind this transdifferentiation are a subject of debate. The survival of patients with NEPC is poor, and few effective treatment options are available. To improve clinical outcomes, understanding of the biology and molecular mechanisms regulating NEPC development is crucial. Various NEPC molecular drivers make temporal contributions during NEPC development, and despite the limited treatment options available, several novel targeted therapeutics are currently under research.

Key points

  • Neuroendocrine prostate cancer (NEPC) is an aggressive variant form that is characterized by low or absent androgen receptor (AR) expression, gain of the neuroendocrine phenotype and is not responsive to therapies targeting AR signalling.

  • De novo NEPC accounts for less than 2% of all prostate cancers, but treatment-induced NEPC occurs in 10–17% of patients with castration-resistant prostate cancer by evolving from adenocarcinoma, probably as a result of a transdifferentiation process.

  • Molecular mechanisms underlying NEPC development include genomic alterations, abnormal regulation of epigenetic regulators, transcription factors and other molecular pathways. The temporal contribution and co-operation of NEPC drivers during adenocarcinoma to NEPC transdifferentiation is largely unknown; thus, longitudinal study of serial patient samples and preclinical models that recapitulate the entire disease progression is warranted.

  • Longitudinal analyses of the only clinically relevant patient-derived xenograft model with serial genomic and transcriptomic data available throughout the adenocarcinoma-to-NEPC transdifferentiation process (LTL331/331 R) could group NEPC-driving molecular alterations into early and terminal events, suggesting their roles during different phases of NEPC development.

  • Platinum-based chemotherapy is the only treatment currently available for NEPC. Advances in NEPC research have led to new potential therapies that are undergoing investigation in clinical trials or in preclinical development.

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Fig. 1: Hypotheses of the origin of neuroendocrine prostate cancer.
Fig. 2: Timing of the emergence of molecular events in the LTL331/LTL331R patient-derived xenograft model of neuroendocrine prostate cancer53,98.

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Acknowledgements

The authors thank all members of the Living Tumor Laboratory (www.livingtumorlab.com) for helpful discussions. This research was supported in part by the Canadian Institutes of Health Research (#141635, #144159, #153081, #173338, Yuzhuo W.), Terry Fox Research Institute (#1062, Yuzhuo W.), Mitacs Accelerate Program (#IT10125, #IT06414, #IT12387, IT14958, Yuzhuo W., NCI grant (P50CA097186) pilot project award (Yuzhuo W.), Prostate Cancer Foundation BC (X.C.), and China Scholar Council award (Yu W.).

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Yong W. and Yu W. researched data for the article, Yong W., Yu W., X.C. and D.L. wrote the article, Yuzhuo W., D.L., Yong W., Yu W., X.C., S.C. and F.C. made a substantial contribution to discussion of the content of the manuscript and Yuzhuo W., D.L., S.Y.C.C. and F.C. reviewed and edited the manuscript before submission.

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Correspondence to Dong Lin or Yuzhuo Wang.

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Nature Reviews Urology thanks A. Lopez-Beltran and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Lineage plasticity

The ability of a cell to convert from one cell type to another, which could refer to the potential of a fully differentiated cell to de-differentiate and then re-differentiate into a different cell lineage status.

Simian virus 40 T antigens

(SV40 T- Ag). Dominant-acting oncoproteins encoded by the polyomavirus SV40, which are capable of inducing malignant transformation of a variety of cell types.

Allelic imbalance

A phenomenon in which the two alleles of a given gene are expressed at different levels in a given cell.

Genomic profiles

Identification of genomic alterations in a particular cell or tissue type.

Divergent clonal evolution

A tumour evolution model, in which different tumour clones share some genetic alterations inherited from a common ancestor cell, but also display unique alterations that are acquired during early evolutionary divergence.

Probasin promoter

The promoter of rat probasin, an androgen-regulated protein, which commonly uses prostate-specific promoters to drive targeting expression of genes of interest to the prostate epithelium.

Transcriptomic profiles

Identification and quantification of RNA transcripts expressed in a particular cell or tissue type.

AR-indifferent status

Sustained growth of prostate tumour cells that is not driven by, or dependent on, canonical AR signalling.

Notch signalling pathway

A highly conserved signalling pathway that occurs through direct interaction between Notch, the receptor, and the Jagged or Delta family of ligands to trigger proteolytic cleavage to release Notch intracellular fragment that functions to regulate transcription.

Human kinome

The complete set of protein kinases expressed in human cells.

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Wang, Y., Wang, Y., Ci, X. et al. Molecular events in neuroendocrine prostate cancer development. Nat Rev Urol (2021). https://doi.org/10.1038/s41585-021-00490-0

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