Abstract 1417: Defining the mechanism of androgen receptor activation by ABI1

Abstract Prostate cancer is the most common non-skin cancer among men worldwide and the second leading cause of cancer-related deaths. Prostate tumor development is driven by androgen receptor (AR) signaling, and while early-stage prostate cancer responds well to anti-androgen therapies, resistance frequently emerges. This resistance often involves aberrant reactivation of AR signaling, underscoring the critical need for a deeper understanding of AR regulation to inform new therapeutic strategies.AR activation is mediated by the intrinsically disordered N-terminal domain (NTD), which contains several proline-rich (PXXP) motifs that serve as consensus sequences for SH3 domain binding. Our previous work identified Abelson-interactor 1 (ABI1) as a novel AR-binding protein via ABI1's SH3 domain. ABI1, a key regulator of the actin cytoskeleton as part of the WAVE complex, exhibits dysregulated expression during prostate cancer progression. We hypothesize that ABI1 regulates AR, and its splice variant AR-V7, through multivalent interactions between ABI1's SH3 domain and PXXP motifs in the AR NTD. To investigate this, we used purified AR PXXP peptides and ABI1-SH3 probes in far-western blotting assays, demonstrating that ABI1-SH3 preferentially binds to two of the seven canonical PXXP motifs within AR-NTD. In vivo studies with AR NTD-truncation mutants further confirmed that ABI1 regulates AR activity through these interactions. These findings position ABI1 as a regulator of AR activity, potentially linking AR dysregulation with cytoskeletal reorganization and cancer cell metastasis. This work enhances our understanding of ABI1's role in AR-driven tumorigenesis and provides a foundation for future studies aimed at targeting ABI1-AR interactions to develop novel therapies for advanced prostate cancer. Citation Format: Kevin Mengen Lin, David M. Solano, Baylee Porter-Hansen, Xiang Li, Leszek Kotula. Defining the mechanism of androgen receptor activation by ABI1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1417.