Abstract 2923: New insights into interactions of the androgen receptor with ELK1 and the platform antagonist KCI807

Abstract

Abstract Prostate cancer (PC) is generally dependent on the androgen signaling axis for growth. Advanced PC is managed by androgen deprivation therapy (ADT). However, the tumors frequently progress by restoring AR signaling that is either androgen-independent or hypersensitive to androgen, leading to castration resistant prostate cancer (CRPC). CRPC is also supported by hormone-independent actions of AR splice variants which lack the ligand binding domain. Additionally, ADT has many undesirable side effects on a variety of normal tissues that depend on androgen for non-growth related functions, including effects on the cardiovascular system, central nervous system (cognitive effects), bone and muscle. Therefore, a more strategic therapy approach would be to disrupt a functional arm of AR-signaling that is critical for PC/CRPC growth but not for the essential physiological roles of AR in normal tissues. Previous studies in this laboratory have identified ELK1 as an AR tethering protein essential for activation of a critical set of androgen/AR growth genes in various PC model cell line models, both in vitro and in vivo, including those resistant to castration and enzalutamide. It was also established that the N-terminal A/B domain of AR binds to ELK1 by co-opting the two ERK docking sites on ELK1 to constitutively activate genes enriched for cell growth functions in PC cells. A platform antagonist (KCI807) was discovered that bound to AR (Kd = 7x10-8 M), blocking its association with ELK1 and inhibiting PC/CRPC tumor growth. KCI807 has a limited target gene set (a subset of AR target genes) that is primarily and highly enriched for functions in cell cycle progression and mitosis. To further drug development, we must identify the ELK1 docking site recognition sites in AR and the KCI807 binding site. Using a variety of complimentary approaches, we have now mapped and validated the ELK1 docking site recognition sites in the AR A/B domain and also the binding site of KCI807 in AR. The two docking site recognition sites in the AR A/B domain for the two docking sites in ELK1 span amino acids 358-456 and amino acids 514-557. We have also developed a working model in which KCI807 binds in a cleft adjacent to the downstream ELK1-binding site, within the DBD, displacing an alpha helix which in turn disrupts ELK1 binding. Further structural and functional studies based on this knowledge will directly aid in design of next-generation antagonists to selectively target ELK1-dependent growth signaling by AR in PC/CRPC tumors. Citation Format: Claire L. Soave, Charles Ducker, Nathan Nicely, Yanfang Huang, Luke Pardy, Peter Shaw, Manohar Ratnam. New insights into interactions of the androgen receptor with ELK1 and the platform antagonist KCI807 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2923.