Abstract
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 devoidof 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.
Highlights
A reduction in phosphoinositide 3-kinase (PI3K)/mammalian target for rapamycin (mTOR) signaling in MCF-7 cells due to the PI3K mutation can compromise their ability to recover from radiation-induced damage
It is demonstrated for MDA-MB-231 and MCF-7 cells that cytotoxicity of NVP-BEZ235 and TAK-165, based on clonogenic survival, is concentration-dependent (Figure 2)
For NVP-BEZ235 treatment, the each inhibitor for 50% cell kill (EC50)-values of 4.25 and 4.15 nM obtained for MDA-MB-231 and MCF-7, respectively, are comparable with PI3K/mTOR inhibition data reported elsewhere for MDA-MB-231 and the human epidermal growth factor receptor 2 (HER-2) amplified breast cancer cell lines BT474 and MDA-MB-175-VII [16,17]
Summary
Dysregulation of downstream components of the HER-2 signaling pathway have been suggested to be responsible for the observed resistance [2] Such resistance may be partly attributable to the heterogeneity in the distribution of target antigen expression in a given cell population, which can lead to the inability to effectively target all cells with toxic levels of therapeutic agents [3]. Another challenge is that some HER-2 positive cancers express a constitutively active truncated form of the protein (p95 HER-2) which does not possess the extracellular domain required for trastuzumab binding [4], and HER-2 targeted treatment may fail. To improve the management of triple-negative breast cancer, effective targeting of malignant cells devoid of ER, PR, and HER-2 expression is warranted
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
