The role of FGF7 in castration resistant prostate cancer.

Abstract

OBJECTIVE: To investigate the development of castration resistant prostate cancer, and the role FGF7 has in enabling these cells to survive. METHODS: A neo adjuvant trial consisting of a “super-castration” treatment with bicalutamide, abiraterone and degarelix treatment for a period of 6 months prior to radical prostactomy was conducted. DNA from 7 pre (formalin fixed paraffin bedded (FFPE)), 20 post (11 FFPE, 9 fresh frozen) and 14 germline (whole blood) samples were used for whole genome sequencing (WGS). Tissue was sequenced at 30X and blood at 15X depth on the Illumina HiTenX. RNA from 6 fresh frozen post treatment samples, and 8 matched hormone naïve samples were used to construct a RNA-Seq library and sequenced at a length of 150 bp using paired end chemistry on an Illumina HiSeq. To validate the findings from the RNA-Sequencing data, LnCaP and LaPC4 cell lines were treated with FGF7, bFGF, TGFβ, and LIF, and the cells proliferation and metabolism was measured using MTT assay. The effect of these proteins on the expression of other genes of interested was measured using qPCR. RESULTS: Although we have found through WGS that there is an increase in single nucleotide variants (SNVs), and copy number variations (CNVs) in post samples as compared to germline and pre samples in some patients, this increase is not observed in other patients with a similar response to treatment. Preliminary RNA-Seq data has detected an epithelial to mesenchymal and a basal cell signature. It has also shown an increased expression in FGF7, and preliminary validation in cell lines treated with FGF7 indicates that it plays a role in the survival of cells when they are in a castrate environment, in addition to altering the expression of genes involved in the epithelial to mesenchymal transition, as well as other genes of interest which were found to have an altered expression in the super castration cohort. CONCLUSIONS: Our results indicate that the development of castration resistant prostate cancer may be due to FGF7 enabling the survival of cells in the presence of a castrate environment.