Inhibition of PI3K and mTOR Sensitises Oestrogen Receptor Positive Human Breast Cancer Cells to a Large Fraction of Radiation Dose
AbstractResistance to radiotherapy has been attributed to the expression of proteins pertinent to cancer cell survival. Treatment approaches that can effectively target these proteins, to possibly augment the effect of radiotherapy, are lacking. This is partly due to the heterogeneity in cellular expression of potential target
proteins like human epidermal growth factor receptor 2 (HER-2), progesterone receptor (PR), and oestrogen receptor (ER). Such heterogeneity can result in an inability to adequately target all cells, and thus treatment failure. Hypofractionated radiotherapy has become a common clinical practice, and developing approaches
that can enhance the effect of this regimen may prove beneficial to cancer management. In this study, an inhibitor of HER-2 (TAK-165) and a dual inhibitor of phosphoinositide-3-kinase (PI3K) and mammalian target of rapamycin (mTOR) (NVP-BEZ235) were tested for their radiomodulatory effects, at 6 Gy, in three human
breast cell lines (MDA-MB-231, MCF-7, MCF-12A) with low expression of HER-2, and different expression levels of ER and PR. Pre-treatment with TAK-165 or a cocktail of TAK-165 and NVP-BEZ235 yielded a modest or no radiosensitisation in all cell lines. NVP-BEZ235 treatment resulted in a significant radiosensitisation of the
ER and PR overexpressing cells (MCF-7), but not in the ER and PR negative cells (MDA-MB-231 and MCF-12A). These results strongly suggest that inhibition of PI3K and mTOR in ER-positive tumours might sensitise them to hypofractionated radiotherapy, and that triple-negative cancers may not benefit from this regimen.
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