Abstract
Resistance 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 targetproteins 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 approachesthat 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 humanbreast 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 theER 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.
Highlights
To investigate whether radiosensitisation of breast cancer cell lines exists at higher fractional doses, as may be encountered in stereotactic radiotherapy, the effect of blocking the activities of human epidermal growth factor receptor 2 (HER-2), PI3K and mammalian target of rapamycin (mTOR), and immediately irradiating cell cultures to 6 Gy was assessed
Pre-treatment of MDA-MB-231 cells (PI3K wild-type) with the HER-2 inhibitor (TAK-165) appeared to increase radioresistance, whilst treatment with either the dual inhibitor of PI3K and mTOR (NVPBEZ235) alone or in combination with TAK-165 resulted in a slight reduction in radiosensitivity (P > 0.38)
While HER-2 inhibition had no effect on the radiosensitivity of the PI3K mutant MCF-7 cell line, inhibition of PI3K and mTOR yielded a 12-fold radiosensitisation (Figure 1 and Table 1)
Summary
Evidence suggests that even at such large fractional doses, the linear-quadratic formalism can be used for estimating the effect of treatment in tumours and normal tissue to the same degree of certainty as in conventional fractionated radiotherapy [10,11,12]. In addition to exhibiting little or no HER-2 activity, these cancers do not express other potential targets like the progesterone receptor (PR) and oestrogen receptor (ER). They tend to overexpress the epidermal growth factor receptor (EGFR) [20]. Targeting residual HER-2 and downstream signalling components of the EGFR family members may further potentiate the therapeutic benefit of stereotactic radiotherapy for triple-negative breast cancer. It was recently demonstrated that inhibition of phosphoinositide-3-kinase (PI3K) and mammalian target of rapamycin (mTOR) sensitised breast and prostate cancer cells to 2 Gy of radiation, whilst protecting normal prostate cells [21,22]
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