Increasing radiosensitivity by the combined inhibition of PARP1 and PI3K in BRCA1-mutated triple negative breast cancer

Abstract

Background: To evaluate the radiosensitizing effect of co-targeting of poly (ADP-ribose) polymerase-1 (PARP1) (AZD2461) and phosphoinositide-3-kinase (PI3K) (LY294002) in breast cancer 1, early onset gene (BRCA1)-mutated triple negative breast cancer (TNBC) treated in vitro. Materials and Methods: We established HCC1937-PARP1 cells by transfection. Cell proliferation, cell viability, cell cycle, and cell apoptosis were measured and analyzed. Western blotting and quantitative real-time polymerase chain reaction assays were performed. Results: The cell viability of HCC1937 and HCC1937-PARP1 cells was significantly decreased under 5 Gy of irradiation. Cell apoptosis was remarkably increased by irradiation, whereas overexpression of PARP1 resulted in substantial resistance to the radiation-induced changes. Combined inhibition of PARP1 and PI3K enhanced radiation-induced apoptosis and significantly inhibited cell proliferation compared with single-agent treatment. The PI3K inhibitor induced changes in the cell cycle distribution, but the PARP1 inhibitor did not. The expression levels of LKB1, PHLPP and INPP4B increased after combined inhibition of PARP1 or PI3K compared with irradiation alone. Moreover, combined inhibition of PARP1 and PI3K resulted in increased expression of INPP4B when compared with that induced by single -agent treatment. Conclusion: Combined inhibition of PARP1 and PI3K might be an effective therapeutic strategy to enhance radiosensitivity in BRCA1mutated TNBC.