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.
JCI insight. 2026 Mar 31 [Epub ahead of print]
Galina Gritsina, Sandip Kumar Rath, Hongshun Shi, Qi Chu, Wanqing Xie, Que Thanh Thanh Nguyen, Sambhavi Senthil, Thomas J Myers, Mehmet A Bilen, Sarah E Fenton, Maha Hussain, David S Yu, Jonathan C Zhao, Jindan Yu
Department of Urology, Emory University School of Medicine, Atlanta, United States of America., Department of Radiation Oncology, Emory University School of Medicine, Atlanta, United States of America., VITRAC Therapeutics LLC, Natick, United States of America., Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, United States of America., Robert H. Lurie Comprehensive Cancer, Northwestern University Feinberg School of Medicine, Chicago, United States of America.