Studies of Anticancer Mechanisms of CFI-400945, Radiation and its Combination in Triple Negative Breast Cancer
Abstract
The triple negative breast cancer (TNBC) subtype confers the poorest prognosis and oncological outcomes. Cancer resistance to radiotherapy is one of the factors underlying poor responses in TNBC. Our laboratory previously demonstrated that radiotherapy in combination with the polo-like kinase 4 (PLK4) inhibitor, CFI-400945, led to synergistic anticancer effects in TNBC models. In this thesis, we explored the potential mechanisms of these anticancer effects in-vitro. We assessed alterations in key proteins participating in DNA-damage responses using immunoblotting and immunohistochemistry, perturbations of cell cycle regulations using flow cytometry, and alterations in the gene expression landscape using transcriptomics. We identified that the combination treatment leads to distinct cell cycle changes, such as G2/M arrest and increased polyploidy, as well as enrichment in various cellular pathways, including ones related to cell death, cell cycle and DNA repair. These results create a solid foundation for further studies of the anticancer mechanisms of CFI-400945 and radiotherapy.