Abstract 2116: Mapping peptides critical for association of the androgen receptor with Elk1

Abstract

Both early stage and advanced prostate tumors are generally dependent on the androgen receptor (AR) for growth. Indeed a major clinical approach in management of the disease is to disrupt the AR signaling in the tumors by androgen ablation and the use of anti-androgen drugs. However, these options present major drawbacks including limited efficacy in advanced disease and many undesirable side effects on non-target tissues. Therefore a more tactical therapy approach would be one that could disrupt a functional arm of AR signaling that is critical for prostate tumor growth but not for the essential physiological roles of AR in normal adult tissues. A considerable amount of evidence suggests that in prostate cancer, androgen/AR signaling is redirected to support tumor growth through the association of AR with critical growth promoting genes via tethering proteins. Our previous studies have identified Elk1, a genetically redundant DNA binding transcription factor, as an AR tethering protein essential for AR-dependent growth in established models of both hormone-dependent prostate cancer and castration recurrent prostate cancer. Elk1 recruits AR to chromatin sites to upregulate a major subset of genes that is strongly and primarily enriched for cell growth functions. Further studies in the lab demonstrate that the A/B domain of the AR alone is capable of co-activation of Elk1, suggesting that Elk1 may also mediate the hormone-independent growth supporting function of AR splice variants. Peptide or small molecule inhibitors of the Elk1-AR interaction may therefore selectively target the growth supporting function of AR in the spectrum of prostate tumors, obviating the need for androgen ablation. Toward this end we undertook to map peptide segment(s) of Elk1and AR that are essential for the Elk1-AR synergy. In this study we used deletional and mutational analysis together with a promotor-reporter assay and a mammalian two-hybrid assay. The results demonstrate that the ability to recruit AR resides largely in the C-terminal activation domain of Elk1 (amino acids 307-428) and that residues within segments 367-428 and 307-337 are essential for this interaction. They also demonstrate that the recruitment of AR by Elk1 does not require Elk1 phosphorylation. Critical sites within the AR-A/B domain required for its association with Elk1 reside in the N-terminal region that is distal to known sites of co-regulator binding. This information will guide the development of peptide inhibitors of Elk1-dependent growth induction by androgen/AR and set the stage for future development of small molecule inhibitors. Citation Format: Rayna Rosati, Mugdha Patki, Venkatesh Chari, Manohar Ratnam. Mapping peptides critical for association of the androgen receptor with Elk1. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2116. doi:10.1158/1538-7445.AM2014-2116