Abstract C38: Whole-genome sequencing of paired androgen-dependent and -independent prostate cancer cell lines: Potential role of novel targets in PI3K and Notch signaling pathways in resistance to hormonal therapy

Abstract

Abstract The growth of the majority of prostate tumors is driven by androgens signaling through the androgen receptor. Most patients initially respond to androgen deprivation therapies such as LHRH analogues and anti-androgens like bicalutamide, but after a varying duration of treatment, patients generally develop resistance to these therapies and their tumor progresses to an androgen independent state. Molecular mechanisms that drive androgen independent disease include mutation and amplification of androgen receptor (AR), androgen-independent activation of AR, and AR-independent mechanisms. The aim of this project was to sequence the entire genome of pairs of cell lines, modeling the progression to androgen independent disease, to increase our understanding of these mechanisms and identify new therapeutic targets. Four ‘parental’ prostate cancer cell lines, all of which are sensitive to hormone deprivation, and an androgen independent derivative of each line, derived either by culturing in bicalutamide or growing in the absence of androgens, were subjected to whole genome sequencing. Genomic variants present in the androgen independent but not the parental lines, presumed to be acquired during the progression to androgen independence, were then identified. To find any commonality between the four different pairings, the derived variants were then mapped to functional biological pathways and their likely impact on protein function predicted. Interestingly, derived mutations in the PI3K and Notch signaling pathways were identified in multiple cell lines. In addition to the analysis of derived mutations, baseline characterization of genomic rearrangements and copy number changes in cell lines highlighted variability in the patterns and prevalence of these events as well as uncovering aberrations in genes known to impact prostate cancer development (PTEN, AR, TMPRSS2 rearrangement). This extensive genome sequencing effort has yielded a deeper understanding of potential pathways and molecular events that occur during the acquisition of resistance to anti-androgen therapy, using in vitro models of prostate cancer. These candidates now require validation in tissue samples from prostate cancer patients and functional assays. Citation Format: Gillian L. Dalgliesh, Joanne L. Hartley, Cary H. O'Donnell, James R. Bradford, Iain McKendrick, Barry R. Davies. Whole-genome sequencing of paired androgen-dependent and -independent prostate cancer cell lines: Potential role of novel targets in PI3K and Notch signaling pathways in resistance to hormonal therapy [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C38.