Abstract Patients with advanced prostate cancer have poorer prognoses, characterized by persistent morbidity and mortality, primarily due to the development of metastatic castration-resistant disease. Recent studies indicate that crosstalk between the YAP1/TEAD and NF-kappa B pathways is critical for cellular biology and disease pathogenesis, including cancer progression, metastasis, and therapeutic relapse. However, the functional association of these oncogenic pathways in prostate cancer remains insufficiently characterized. This study aims to evaluate the effects of two pharmacological inhibitors: TED-347, a selective YAP1/TEAD inhibitor, and genistein, a phytoestrogen that inhibits NF-kappa B signaling, on prostate cancer growth in both cell culture and animal models. Both TED-347 and genistein result in substantial reductions in prostate tumor cell growth in vitro and in vivo. Mechanistically, TED-347 and genistein decrease the expression and activity of YAP1/TEAD and NF-kappa B/RELA in prostate xenografts. These reductions are accompanied by decreased expression of cancer stem cell markers CD44, CXCR4, and ALDH1A1, as shown by immunohistochemistry, suggesting impaired self-renewal and tumor-initiating capacity. Treatment with these agents also increased CDKN1A expression, reduced Ki-67 staining, and significantly elevated cleaved caspase-3 levels. Notably, our data also reveal that genistein attenuates the interaction between RELA and TEAD, a process mediated by YAP1. These findings provide mechanistic insights into how TED-347 and genistein suppress prostate cancer cell growth and induce cell death, directly linking these agents to reduced tumor progression, metastasis, and therapeutic relapse. The molecular reprogramming induced by TED-347 and genistein leads to increased apoptosis and reduced tumor viability, supporting their potential as therapeutic strategies for treatment-resistant prostate cancer and justifying further investigation in preclinical and clinical settings. Citation Format: Sebnem Unlu, Abdulrahman M. Dwead, Marwah M. Al-Mathkour, Bekir Cinar. Pharmacological disruption of YAP1/TEAD and NF-kappa B crosstalk suppresses prostate cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7117.
Unlu et al. (Fri,) studied this question.