Prostate cancer cell adaptation to profound androgen suppression

Abstract

Androgen deprivation therapy is the mainstay of treatment for advanced prostate cancer. Although castration results in tumour regression and symptom relief in the majority of cases, the effects are short lived, with most patients demonstrating castration resistant progression within 1-3 years. Numerous molecular mechanisms have been implicated in the development of this resistance to treatment, including maintenance of intraprostatic testosterone levels and changes in the expression of and/or alternative splicing of the androgen receptor. Many of these observations however have been made in cell lines and/or xenograft models, which do not necessarily recapitulate the complex microenvironment in which clinical resistance develops. Whole Genome Sequencing (WGS) and RNASeq has been performed on samples from a cohort of patients who received neo-adjuvant androgen deprivation therapy prior to prostatectomy, and had varying responses, to elucidate the genomic drivers of castration resistant disease. WGS analysis has shown no commonality in neither Single Nucleotide Variations or Copy Number Variations in each response group, nor a distinct change between the pre and post-treatment samples indicating that there is not a selection for a resistant sub clone as a result of androgen deprivation treatment. Analysis of RNA-Seq data has shown no overexpression of the androgen receptor, nor the presence of ARV7. It has however shown a striking difference between treated and untreated samples, displaying a phenotypic change which has occurred as a response to treatment; including an epithelial to mesenchymal transition signature and basal cell signature; as well as an up-regulation in expression of FGF7 and FGF2. Cell line validation assays have indicated that these may be playing a role in treatment persistence in a castrate environment.