AURKA inhibitor VIC-1911 induces mitotic defects and functional BRACness, sensitizing prostate cancer to PARP inhibition

VIC-1911, formerly known as TAS-119, is a next-generation, ATP-competitive AURKA inhibitor with high selectivity over AURKB and AURKC. In this study, we demonstrate that VIC-1911 potently and selectively inhibits AURKA signaling in diverse prostate cancer (PC) cell models, including both androgen receptor (AR)-positive and AR-negative cell lines. VIC-1911 treatment suppressed AURKA phosphorylation and downstream effectors at nanomolar concentrations without affecting AURKB/C activity, resulting in mitotic defects, DNA double-strand breaks (DSBs), and apoptosis. Transcriptomic profiling and immunofluorescence analysis revealed robust activation of DNA damage response pathways and the p53 pathway, consistent with mitotic catastrophe-induced genotoxic stress. Functionally, VIC-1911 significantly inhibited PC cell proliferation and tumor growth in xenograft models, including castration-resistant and AR-negative tumors. Given its ability to induce DNA damage, we evaluated the combinatorial effect of VIC-1911 with PARP inhibitors (PARPi). The combination exhibited synergistic anti-tumor effects in vitro and in vivo, leading to enhanced mitotic abnormalities, γH2AX accumulation, and cleaved PARP expression, even in homologous recombination (HR)-proficient settings. Importantly, VIC-1911 monotherapy and its combination with PARPi were well tolerated in vivo. These findings position VIC-1911 as a promising therapeutic agent for advanced prostate cancer, either as monotherapy or in combination with PARPi to broaden clinical efficacy beyond HR-deficient tumors