Prostate cancer (PCa) is a clinically heterogeneous disease and current treatment strategies are based largely on anatomical and pathological parameters. In the recent past, several DNA sequencing studies of primary and advanced PCa have revealed recurrent patterns of genomic aberrations that expose mechanisms of resistance to available therapies and potential new drug targets. Suppression of androgen receptor (AR) signalling is the cornerstone of advanced prostate cancer treatment. Genomic aberrations of the androgen receptor or alternative splicing of its mRNA are increasingly recognized as biomarkers of resistance to AR-targeted therapy such as abiraterone or enzalutamide. Genomic aberrations of the PI3K-AKT axis, in particular affecting PTEN, are common in PCa, and compounds targeting different kinases in this pathway are showing promise in clinical trials. Both germline and somatic defects in DNA repair genes have been shown to sensitize some patients to therapy with PARP inhibition. In addition, abnormalities in mismatch-repair genes associate with response to immune checkpoint inhibition in other solid tumours and present a tantalizing therapeutic avenue to be pursued. Aberrations in CDK4/6-RB1 pathway genes occur in a subset of PCa, may associate with differential sensitivity to treatment, and are likely to have clinical implications beyond prognostication. Inhibitors of CDK4/6 are already being tested in prostate cancer clinical trials. Furthermore, deletions of RB1 strongly associate with a neuroendocrine phenotype, a rare condition characterised by a non-AR driven transcriptomic profile. Finally, aberrations in genes involved in regulating the chromatin structure are an emerging area of interest. Deletions of CHD1 are not infrequent in PCa and may associate with increased AR activity and genomic instability, and these tumours could benefit from DNA damaging therapies. This review summarizes how genomic discoveries in PCa are changing the treatment landscape of advanced CRPC both by identifying biomarkers of resistance and vulnerabilities to be targeted.
The Journal of pathology. 2016 Oct 18 [Epub ahead of print]
Daniel Nava Rodrigues, Gunther Boysen, Semini Sumanasuriya, George Seed, Angelo M De Marzo, Johann de Bono
The Institute of Cancer Research, 15 Cotswold Road, London SM2 5NG, UK. ., The Institute of Cancer Research, 15 Cotswold Road, London SM2 5NG, UK., Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287., The Institute of Cancer Research, 15 Cotswold Road, London SM2 5NG, UK. .