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

Abstract

VIC-1911 (formerly TAS-119) is a next-generation, ATP-competitive Aurora kinase A (AURKA) inhibitor with a favorable biosafety profile. However, it has not been evaluated in prostate cancer (PC), wherein AURKA is highly expressed in advanced stages and represents a critical therapeutic target. Here, we demonstrate that VIC-1911 potently inhibits AURKA activity with high selectivity over AURKB/C across diverse PC cell lines. Treatment with VIC-1911, even at nanomolar concentrations, substantially inhibits the growth of both androgen receptor (AR)-positive and AR-negative PC cells. VIC-1911 triggers mitotic failure, induces DNA double-strand breaks (DSBs), and activates the p53 pathway, halting cell division and inducing cell death. Notably, VIC-1911 showed synergistic effects in inhibiting PC cell growth in vitro and xenograft tumor growth in vivo with poly (ADP-ribose) polymerase inhibitors (PARPi), which have proven effective in PC with a deficiency in Homologous Recombination (HR) repair. Mechanistically, VIC-1911 disabled HR-mediated repair of DSBs in otherwise HR-proficient PC cells, leading to a "BRCAness" phenotype and pronounced accumulation of DNA damage and mitotic catastrophe. In summary, our study uncovers what we believe a novel mechanism to functional "BRCAness" by inducing mitotic arrest and highlights VIC-1911 as a promising therapeutic agent for advanced PC, either as a single agent or in combination, sensitizing HR-proficient tumors to PARP inhibitors.