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 elucidate the anti-cancer mechanisms in bladder cancer. TAK-901 exhibited a dose-dependent inhibition of proliferation, colony formation, and migration, as well as induction of apoptosis in T24 and UMUC-3 cells. Additionally, bladder cancer cells undergo cell cycle arrest at the G2/M phase when exposed to TAK-901. Mechanistic studies revealed that the targeted inhibition of EGFR by TAK-901 impacted AKT and FOXO3a phosphorylation, leading to the activation of FOXO-dependent transcriptional activity, which subsequently triggered apoptotic pathways through inducing BIM expression. Furthermore, our study demonstrated that TAK-901 attenuated tumor growth in the UMUC-3-Luc 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.