Combined Inhibition of PI3K, mTOR and Bcl-2 Significantly Radiosensitises Progesterone and Oestrogen Receptor Negative Breast Cancer Cells

Abstract

Patients with triple-negative breast cancers (TNBC) constitute about one-fifth of all breast cancer patients. TNBC is an aggressive and heterogeneous disease entity in comparison with other types of breast cancer and, therefore, tends to be resistant to existing treatment regimens, such as, targeted and hormone therapies. There is evidence to suggest that proliferative and survival pathways of triple-negative tumours are still poorly understood, which could be the reason for the observed treatment resistance. Novel treatment approaches are, therefore, needed to overcome the challenges in the treatment of triple-negative breast cancers. Three human breast cell lines (MDAMB- 231, MCF-7 and MCF-12A) were pre-treated ith inhibitors of phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), and the pro-survival gene (Bcl-2), and their radiosensitivities were evaluated using the clonogenic cell survival assay. Inhibition of PI3K, mTOR, and Bcl-2 with a cocktail of small molecule inhibitors NVP-BEZ235 and ABT-263 resulted in a 4- to 14-fold radiosensitisation of human breast cell lines with features similar to those of triple-negative cancers. These findings suggest that inhibition of I3K, mTOR, and Bcl-2 can significantly enhance the sensitivity of breast cells devoid of progesterone and oestrogen receptor expression. This approach may have therapeutic potential for breast cancer management.