AURKA inhibitor VIC-1911 induces mitotic defects and functional BRCAness, sensitizing prostate cancer to PARP inhibition
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
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
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Research Article Genetics Oncology

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 (PCa), 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 PCa cell lines. Treatment with VIC-1911, even at nanomolar concentrations, substantially inhibits the growth of both androgen receptor–positive (AR-positive) and AR-negative PCa 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 PCa cell growth in vitro and xenograft tumor growth in vivo with poly (ADP-ribose) polymerase inhibitors, which have proven effective in PCa with a deficiency in homologous recombination (HR) repair. Mechanistically, VIC-1911 disabled HR-mediated repair of DSBs in otherwise HR-proficient PCa cells, leading to a “BRCAness” phenotype and pronounced accumulation of DNA damage and mitotic catastrophe. In summary, our study uncovers what we believe is a novel mechanism to induce functional BRCAness through mitotic arrest and highlights VIC-1911 as a promising therapeutic agent for advanced PCa, either as a single agent or in combination, sensitizing HR-proficient tumors to PARP inhibitors.

Authors

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

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Figure 6

VIC-1911 significantly inhibits PCa tumor growth either as a single agent or in combination with PARPi.

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VIC-1911 significantly inhibits PCa tumor growth either as a single agen...
(A) VIC-1911 delays AR-positive CRPC tumor growth: 22Rv1 cells were s.c. injected into the right flank of Nod-SCID mice. Once tumors reached approximately 100 mm3, the mice were treated with either VIC-1911 (60 mg/kg) or vehicle for 2 weeks. Tumor growth data are shown as mean ± SEM. ****P < 0.0001, 2-way ANOVA repeated-measures test combined with Bonferroni’s multiple-comparison test. Arrow indicates starting point of treatment. (B) VIC-1911 delays AR-negative CRPC tumor growth. LuCaP93 patient-derived xenograft was s.c. grafted in flanks of Nod-SCID mice on both sides. Once the tumors reached approximately100 mm3, mice were started on treatment with either VIC-1911 (60 mg/kg) or vehicle for 2 weeks. Tumor growth data are shown as mean ± SEM. **P < 0.01, 2-way ANOVA repeated-measures test combined with Bonferroni’s multiple-comparison test. Arrow indicates starting point of treatment. (C) Representative IHC images confirm the reduction of phospho-AURKA in VIC-1911–treated tumors and increased staining for cleaved caspase-3, an apoptosis marker. Synaptophysin (SYP) staining validates the neuroendocrine phenotype of the AR-negative CRPC tumors of LuCaP93. Scale bar: 30 μm. (D) 22Rv1 (0.5 × 106) cells were s.c. injected into the right flanks of Nod-SCID mice. Sixteen days after inoculation, mice were treated with either vehicle, olaparib (50 mg/kg), VIC-1911 (30 mg/kg), or a combination of both for 2 weeks. Tumor growth data are shown as mean ± SEM. *P < 0.05, 2-way ANOVA repeated-measures test combined with Bonferroni’s multiple-comparison test. (E) Representative IHC images of tumor sections stained for Ki67 or phospho-γH2AX (S139) are shown. Scale bar: 30 μm. (F) A model depicting VIC-1911 induction of functional BRCAness, sensitizing PCa cells to PARP inhibitors. VIC-1911 triggers G2/M arrest and mitotic defects, thereby compromising HR repair of DSBs induced by VIC-1911 itself and by PARPi, leading to massive accumulation of DNA damage and mitotic catastrophe and synergistically inhibiting tumor growth.