Triple-negative (TN) breast cancers account for 15%-20% of all breast cancers with limited treatment options and poor prognosis. The poor outcomes seen with TN breast cancers (TNBCs) are in part due to a lack of viable therapeutic targets. Overexpression of insulin-like growth factor 1 receptors results in mammary tumorigenesis and is common in breast carcinomas. However, the use of IGF1R inhibitor alone has produced limited effects on TNBC cells inhibition. NVP-BEZ235 is a potent PI3K/mTOR dual inhibitor and has been shown to be effective in TNBC cell lines, especially for the mesenchymal-like and luminal-androgen receptor subtypes. Unlike rapamycin, which produces a feedback activation of Akt, NVP-BEZ235 alone successfully blocks the Akt activation and effectively inhibits the cells proliferation. Methods: In this study, we examined the effects of a selective IGF1R small molecule inhibitor picropodophyllin (PPP) in combination with NVP-BEZ235 on human MDA-MB-231, MDA-MB-468, HCC1806 and BT549 TNBC cell lines. SRB cell survival assays were performed following PPP or NVP-BEZ235 treatments alone and PPP in combination with NVP-BEZ235. Western blotting was used to detect expression and phosphorylation of down-stream signaling proteins and fluorescence-activated cell sorting (FACS) analysis to assess effects on apoptosis following treatments. Results: The combined IGF1R inhibition with PPP and PI3K/mTOR inhibition with NVP-BEZ235 resulted in significantly greater cytotoxicity than either PPP or NVP-BEZ235 alone in all four cell lines compared to single agent treatments. Notably, this difference was more pronounced at lower concentrations of both drugs (between 7.8 nM-62.5 nM). The combination of PPP and NVP-BEZ235 inhibitors also significantly increased apoptosis via induction of cleaved caspase-3 and suppressed the PI3K/Akt and MEK/ERK signaling cascades in these TNBC cell lines. Conclusion: These results suggest that the combined inhibition of IGF1R and PI3K/mTOR may be a more effective strategy than single inhibition for TNBC treatments and warrant further investigation in in vivo animal studies.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-11-06.