Exploring the therapeutic vulnerability of castration-resistant prostate cancer via Hippo-YAP/TAZ-TEAD signaling

Background: The Hippo-YAP/TAZ-TEAD signaling axis is frequently upregulated in many cancers, including subsets of prostate cancer (PCa). However, its role in therapy resistance remains incompletely understood. In this study, we investigated the therapeutic potential of targeting YAP/TAZ-TEAD signaling in PCa, with an emphasis on androgen-independent and enzalutamide-resistant disease. Methods: LNCaP, PC3, and DU145 cells were obtained from ATCC. Enzalutamide-resistant lines (LNCaP-ENZR/PCaNO1 and C4-2-ENZR/PCaNO2) were generated by culturing LNCaP and C4-2 cells with 5 µM enzalutamide for >6 months. mRNA expression was quantified by qRT-PCR, and protein levels were examined by western blotting. Anti-tumor effects of YAP/TAZ-TEAD inhibitors (GNE-7883, K-975) were assessed using IncuCyte live-cell imaging for proliferation; long-term survival was measured by colony formation assays. Cell migration and invasion were evaluated using scratch-wound healing and Matrigel transwell assays, respectively. Results: Androgen-independent PCa cells (PC3 and DU145) exhibited marked upregulation of YAP/TAZ-TEAD transcriptional targets compared to LNCaP cells. Enzalutamide-resistant PCaNO1 and PCaNO2 cells displayed strong induction of YAP/TAZ-TEAD target genes and increased YAP1, TAZ, and TEAD protein levels relative to parental controls. Enzalutamide resistance was also associated with elevated PD-L1 expression. Pharmacologic inhibition of YAP/TAZ-TEAD signaling significantly suppressed cell growth and proliferation, and reduced colony formation, migration, and invasion across PCa models. Ongoing experiments are assessing the impact of YAP/TAZ-TEAD inhibition on PD-L1 regulation. Conclusion: YAP/TAZ-TEAD inhibitors effectively block proliferation and invasiveness of prostate cancer cells, including enzalutamide-resistant models. These findings support YAP/TAZ-TEAD signaling as a promising therapeutic vulnerability and potential strategy to overcome therapy resistance in subsets of advanced prostate cancer.