TAK-901 Targeted Inhibition of EGFR Activates Transcription Factor FOXO, Causing Cell-cycle Arrest and Apoptosis in Bladder Cancer

Bladder cancer is the most prevalent malignancy of the urinary tract, characterized by an unfavorable prognosis, elevated rates of recurrence, and a lack of targeted therapeutic approaches. In this research, we evaluated the efficacy of TAK-901, a specific inhibitor targeting Aurora kinase, and elucidated the anticancer mechanisms in bladder cancer. TAK-901 exhibited a dose-dependent inhibition of proliferation, colony formation, and migration, as well as the induction of apoptosis in T24 and UMUC-3 cells. Additionally, bladder cancer cells underwent cell-cycle arrest at the G2-M-phase when exposed to TAK-901. Mechanistic studies revealed that the targeted inhibition of epidermal growth factor receptor (EGFR) by TAK-901 affected AKT and forkhead box class O3a (FOXO3a) phosphorylation, leading to the activation of FOXO-dependent transcriptional activity, which subsequently triggered apoptotic pathways by inducing BIM expression. Furthermore, our study demonstrated that TAK-901 attenuated tumor growth in the UMUC-3-luciferase xenograft model and significantly reduced Ki-67 expression in tumor tissues. Finally, we propose a novel treatment strategy involving the synergistic inhibition of bladder cancer cell growth by combining TAK-901 with afatinib. Our research strongly suggests that Aurora A and Aurora B are promising epigenetic therapeutic targets in bladder cancer. Furthermore, TAK-901 can function as a targeted kinase inhibitor and EGFR inhibitor for the treatment of bladder cancer by activating the FOXO signaling pathway, which induces apoptosis in bladder cancer cells.