Role of AURKB Inhibition in Reducing Proliferation and Enhancing Effects of Radiotherapy in Triple-Negative Breast Cancer

Abstract

Breast cancer is a leading cause of cancer-related deaths in females. Triple-negative breast cancer (TNBC) subtype is the most aggressive form of breast cancer that lacks biomarkers and effective targeted therapies. Its high degree of heterogeneity as well as innate and acquired resistance to treatment creates further barriers in achieving positive clinical outcomes in TNBC. Thus, development of novel treatment approaches in TNBC is of high clinical significance. Multimodality approaches with targeted agents and radiotherapy (RT) are promising for increasing efficacy of treatment and circumventing resistance. Here we examined anticancer effects of the Aurora Kinase B (AURKB) inhibitor AZD1152 as a single agent and in combination with RT using various TNBC cell lines, MDA-MB-468, MDA-MB-231 and SUM-159. We observed that AZD1152 alone effectively inhibited colony formation in TNBC cell lines. The combination of AZD1152 at IC50 concentrations together with ionizing radiation further reduced colony formation as compared to the single agent treatment. Our data support the notion that inhibition of the AURKB pathway is a promising strategy for treatment and radiosensitization of TNBC and warrants further translational studies.

Keywords: AURKB; AZD1152; Aurora Kinase B; breast cancer; combination treatment; multimodality treatment; radiation.

Figure 1

Effects of single agent AZD1152 at increasing concentrations on colony formation in TNBC cell lines. Dose response curves were generated for AZD1152 in studied cell lines. IC50 values were determined using a nonlinear regression model in GraphPad Prism software.

Figure 2

Effects of AZD1152 in combination with RT in TNBC cell lines. Combination treatment of (A) MDA-MB-231; (B) MDA-MB-468; (C) SUM159 cells with a single concentration of AZD1152 and a single dose of RT. Treatment with RT or AZD1152 alone results in reduced colony formation with further significant reduction of proliferation by a combination treatment relative to single agent treatment (p≤0.05 compared to control (*), RT only (^⍺) or (^β) AZD1152 only treatment); (D) Synergy plot using various concentrations of AZD1152 and doses of RT in MDA-MB-231 cells using SynergyFinder, where the intensity of red indicates a higher degree of synergy (n = 3).