Abstract 560: Characterizing the role of TIAM1-Rac1 signaling in advanced prostate cancers

Abstract Background: Roughly 20-30% of patients with castration-resistant prostate cancer (CRPC) will progress to neuroendocrine prostate cancer (NEPC) following treatment of androgen receptor signaling inhibitors (ARSIs) such as enzalutamide and abiraterone. NEPC is an aggressive, treatment-resistant form of prostate cancer (PCa) with an average survival time of ∼7 months post-diagnosis. Poor understanding of acquired resistance mechanisms and disease progression prevents the development of efficacious treatments for advanced PCa (NEPC and CRPC). The Rac1-associated guanine nucleotide exchange factor TIAM1—identified as a novel neural lineage signature in enzalutamide-resistant PCa cells—promotes the survival of neuroendocrine small-cell lung cancer. Here, we interrogate how TIAM1 contributes to acquired resistance and disease progression in advanced PCa. Methods: RNA-seq, GEO, and cBioPortal datasets were analyzed to assess the relationships between TIAM1 expression and enzalutamide treatment, patient survival, and androgen receptor dependency. Cell growth assays determined the effects of TIAM1-specific RNA interference and TIAM1 overexpression in CRPC and NEPC-like cell lines. TIAM1 expression was evaluated using real-time quantitative PCR. Results: Analysis of publicly available datasets revealed patients and mice treated with enzalutamide showed increased TIAM1 mRNA expression and that high relative TIAM1 mRNA expression significantly correlated to poor disease-free survival. NEPC and NEPC-like cell lines exhibited higher average TIAM1 mRNA expression than CRPC cells. siRNA TIAM1 depletion in drug-resistant NEPC-like cells showed moderate re-sensitization to the ARSIs enzalutamide and abiraterone. Transient TIAM1 overexpression in CRPC cells conferred partial tolerance to enzalutamide compared to vehicle-treated cells. Conclusions: These results establish the clinical relevancy of TIAM1 in PCa models. Long-term treatment with enzalutamide increased TIAM1 expression in patient and murine samples, possibly contributing to acquired resistance mechanisms as demonstrated by increased ARSI sensitivity upon TIAM1 depletion. Current efforts in our lab focus on elucidating the mechanistic contributions of the TIAM1-Rac1 axis in acquired ARSI resistance to facilitate synergistic treatment of advanced PCa. Citation Format: James P. Maine, Masuda Sharifi, Shu Ning, Amy R. Leslie, Zachary A. Schaaf, Wei Lou, Allen C. Gao. Characterizing the role of TIAM1-Rac1 signaling in advanced prostate cancers [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 560.