Intrinsic tumour radioresistance limits the benefit of radiotherapy. Targeted treatment modalities that are singly effective for triple-negative breast cancer are lacking, partly due to paucity of relevant targets as they are devoid of the human epidermal growth factor receptor 2 (HER-2), progesterone receptor (PR), and oestrogen receptor (ER); or to resistance to single-target therapies as a consequence of cellular heterogeneity. Concomitant targeting of cell signaling entities other than HER-2, PR and ER may sensitise triple-negative tumours to radiotherapy. In this study, we investigated the effect of an HER-2 inhibitor (TAK-165) and a dual inhibitor of phosphoinositide 3-kinase (PI3K) and mammalian target for rapamycin (mTOR) (NVP-BEZ235) in three human breast cancer cell lines. The potential of simultaneous inhibition of HER-2, PI3K and mTOR with a cocktail of the specific inhibitors TAK-165 and NVP-BEZ235, to radiosensitise human breast cancer cells in vitro was examined using the colony forming assay. Combined inhibition of HER-2, PI3K, and mTOR resulted in significant radiosensitisation in all cell lines, independent of HER-2, ER, or PR status. Radiosensitisation was more prominent in ER-and PR-negative cells expressing higher levels of epidermal growth factor receptor (EGFR). These data suggest that a cocktail of TAK-165 and NVP-BEZ235 could potentially be effective in the treatment of triple-negative breast cancer.

Targeted therapy for prostate cancer may offer potential improvement over current conventional therapies because of its specificity. Although conventional treatments are effective, they are not always curative, andhave several limitations. In prostate cancer, activation of the epidermal growth factor receptor (EGFR) and the phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathways have been implicatedin tumorigenesis, and resistance to both conventional and targeted anticancer therapies. Single-target therapies may fail due to cellular heterogeneity. Concomitant targeting of EGFR and PI3K/mTOR cell signaling components may enhance the efficacy of radiotherapy. In this study, the effect of an EGFR inhibitor (AG-1478) and a dual inhibitor of PI3K and mTOR (NVP-BEZ235) on the radiation response of a human prostate carcinoma cell line (DU145) and a normal prostate cell line (1542N) was investigated, using the colony forming assay. Treatment ofDU145 cells with AG-1478 and NVP-BEZ235, either singly or in combination, resulted in a slight radiosensitisation of DU145 cells. Neither AG-1478 nor a cocktail of both inhibitors had an effect on the radiation response of the 1542N cell line. Interestingly, NVP-BEZ235 significantly protected 1542N cells from radiation-induced cell death. These data suggest that a specific inhibitor of PI3K and mTOR (NVP-BEZ235) could potentially be effective as a radio-protector.

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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.