Targeting the adaptive molecular landscape of castration-resistant prostate cancer.

Alexander W Wyatt,Martin E Gleave

doi:10.15252/emmm.201303701

Alexander W Wyatt, Martin E Gleave

Open Access

https://doi.org/10.15252/emmm.201303701

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Journal: EMBO molecular medicine	Publication Date: Apr 20, 2015
Citations: 115	License type: CC BY 4.0

Affiliation: University of British Columbia

Abstract

Castration and androgen receptor (AR) pathway inhibitors induce profound and sustained responses in advanced prostate cancer. However, the inevitable recurrence is associated with reactivation of the AR and progression to a more aggressive phenotype termed castration-resistant prostate cancer (CRPC). AR reactivation can occur directly through genomic modification of the AR gene, or indirectly via co-factor and co-chaperone deregulation. This mechanistic heterogeneity is further complicated by the stress-driven induction of a myriad of overlapping cellular survival pathways. In this review, we describe the heterogeneous and evolvable molecular landscape of CRPC and explore recent successes and failures of therapeutic strategies designed to target AR reactivation and adaptive survival pathways. We also discuss exciting areas of burgeoning anti-tumour research, and their potential to improve the survival and management of patients with CRPC.

Highlights

Normal prostate epithelial cells become malignant through deregulation to context-specific tumour suppressors and oncogenes (Taylor et al, 2010; Barbieri et al, 2012; Baca et al, 2013)
The precise combination of genomic aberrations is notoriously heterogeneous between patients (Wyatt et al, 2014), at diagnosis the most common events include rearrangements affecting ETS gene family members, mutations in the ubiquitin ligase SPOP, disruption to the PI3K antagonist PTEN and copy number gain of oncogenic transcription factor MYC (Taylor et al, 2010; Barbieri et al, 2012)
True to its hormone-regulated non-malignant ancestor, prostate cancer cells remain dependent on a ligand-activated androgen receptor (AR) to facilitate mitogenic responses enabled by genomic aberration

Summary

Introduction

Normal prostate epithelial cells become malignant through deregulation to context-specific tumour suppressors and oncogenes (Taylor et al, 2010; Barbieri et al, 2012; Baca et al, 2013). AR-Vs detected in circulating tumour cells from CRPC patients have been recently associated with resistance to abiraterone and enzalutamide (Antonarakis et al, 2014).

Results

Conclusion