MLN8054, a small molecule inhibitor of aurora kinase a, sensitizes androgen-resistant prostate cancer to radiation

Purpose: To determine whether MLN8054, an Aurora Kinase A (Aurora-A) inhibitor causes radiosensitization in androgen-insensitive prostate Cancer cells in vitro and in vivo.

Methods and materials: In vitro studies consisted of culturing PC3 and DU145 prostate Cancer cells and then immunoblotting Aurora A and phospho-Aurora A after radiation and/or nocodazole with MLN8054. Phases of the cell cycle were measured with flow cytometry. PC3 and DU145 cell lines were measured for survival after treatment with MLN8054 and radiation. Immunofluorescence measured γ-H2AX in the PC3 and DU145 cells after treatment. In vivo studies looked at growth delay of PC3 tumor cells in athymic nude mice. PC3 cells grew for 6 to 8 days in mice treated with radiation, MLN8054, or combined for 7 more days. Tumors were resected and fixed on paraffin and stained for von Willebrand factor, Ki67, and Caspase-3.

Results: In vitro inhibition of Aurora-A by MLN8054 sensitized prostate Cancer cells, as determined by dose enhancement ratios in clonogenic assays. These effects were associated with sustained DNA double-strand breaks, as evidenced by increased immunofluorescence for γ-H2AX and significant G2/M accumulation and polyploidy. In vivo, the addition of MLN8054 (30 mg/kg/day) to radiation in mouse prostate Cancer xenografts (PC3 cells) significantly increased tumor growth delay and Apoptosis (Caspase-3 staining), with reduction in cell proliferation (Ki67 staining) and vascular density (von Willebrand factor staining).

Conclusion: MLN8054, a novel small molecule Aurora-A inhibitor showed radiation sensitization in androgen-insensitive prostate Cancer in vitro and in vivo. This warrants the clinical development of MLN8054 with radiation for prostate Cancer patients.