Anticancer Effects and Mechanisms of CFI-400945 and Radiation in Breast Cancer
Abstract
Breast cancer is a leading cause of death in women and development of new treatments is essential. Polo-like Kinase 4 (PLK4) controls centriole duplication and its inhibition by CFI-400945 induces genomic instability and aneuploidy. Radiation therapy (RT) also induces aneuploidy leading to cell death, although development of radioresistance is common. We hypothesized that CFI-400945 and RT act synergistically in breast cancer. Colony formation assays identified synergistic anticancer effects of CFI-400945 and RT, with combinatorial effects also observed for RT with either siRNA inhibition of PLK4 or with the PLK4 inhibitor Centrinone B. This suggests that the antiproliferative effect of these combinations are, at least partly, mediated through PLK4. Immunocytochemistry for Centrin showed significant overamplification of centrioles in combination compared to single agent treatment, suggesting a possible combined mechanism of action. These results support further translational studies of CFI-400945 and RT as a combination treatment to improve breast cancer outcomes.