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Lorenzin et al. J Transl Genet Genom 2019;3:5 Journal of Translational
DOI: 10.20517/jtgg.2019.01 Genetics and Genomics

Review Open Access

Evolution of the prostate cancer genome towards
resistance

Francesca Lorenzin , Francesca Demichelis 1,2
1
1 Department of Cellular, Computational and Integrative Biology, University of Trento, Trento 38123, Italy.
2 Englander Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medicine, New York, NY 10065, USA.
Correspondence to: Prof. Francesca Demichelis, Department of Cellular, Computational and Integrative Biology, University of Trento,
Via Sommarive 9, Trento 38123, Italy. E-mail: f.demichelis@unitn.it

How to cite this article: Lorenzin F, Demichelis F. Evolution of the prostate cancer genome towards resistance. J Transl Genet Genom
2019;3:5. https://doi.org/10.20517/jtgg.2019.01
Received: 20 Jan 2019 First Decision: 22 Jan 2019 Revised: 30 Jan 2019 Accepted: 1 Feb 2019 Published: 12 Mar 2019

Science Editor: David N. Cooper Copy Editor: Cai-Hong Wang Production Editor: Huan-Liang Wu

Abstract

The clinical behavior of prostate cancer is highly heterogeneous, with most patients diagnosed with localized disease
that successfully responds to surgery or radiotherapy or that can be followed by active surveillance. However, a fraction
of men will relapse after initial treatment and eventually progress to an aggressive resistant form with metastasis
spreading and high mortality, a state referred to as castration resistant prostate cancer (CRPC). The technological
advances in next generation sequencing have enabled the deep genomic and epigenomic characterization of both the
hormone naïve and CRPC states, leading to the definition of molecular subclasses of prostate cancer that could inform
the clinicians on therapeutic strategies. These studies also shed light on the mechanisms driving resistance to therapy.
CRPCs adapt to androgen receptor (AR) signaling impairment - which follows first-line therapies as androgen deprivation
or AR targeting - by restoring the nuclear receptor signaling by means of multiple mechanisms. Alternatively, tumor cells
might become resistant to targeted therapies by exploiting lineage plasticity and activating alternative pathways. This
review will discuss the main mechanisms leading to the emergence of resistance to therapy in prostate cancer patients
in the context of genomic and molecular features of CRPC and on their causal role in the development of resistance.

Keywords: Prostate cancer, cancer evolution, resistance mechanisms, androgen receptor, metastases, castration resistant
prostate cancer, genomics, epigenetics

INTRODUCTION
Prostate cancer (PCa) is the most common malignancy diagnosed among men in the US and is a major
[1]
cause of death with 164,690 new estimated cases in 2018 and 29,430 expected deaths . PCa is a clinically

© The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long
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