Abstract P5-07-07: Combination of IGF1R/FAK inhibition and PI3K/mTOR inhibition in triple-negative breast cancers

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Abstract Introduction: Triple-negative breast cancers (TNBCs) account for 15%-20% of all breast cancers with limited treatment options and poor prognosis. The poor outcomes seen with TNBCs are in part due to a lack of viable therapeutic targets. Overexpression of insulin-like growth factor 1 receptors (IGF1R) and focal adhesion kinase (FAK) are closely associated with invasive breast carcinomas. However, in our previous study, we found that the combined use of IGF1R inhibitor and FAK inhibitor had 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. Our hypothesis is that the combined inhibition of IGF1R/FAK and PI3K/mTOR produces greater suppression on TNBC cell growth. Methods: We examined the effects of NVP-TAE226, the dual inhibitor of IGF1R and FAK, in combination with NVP-BEZ235 on human MDA-MB-231 and BT549 TNBC cell lines. SRB cell survival assays were performed following NVP-TAE226 or NVP-BEZ235 treatments alone and NVP-TAE226 in combination with NVP-BEZ235. Western blotting was used to detect expression and phosphorylation of down-stream signaling proteins and epithelial to mesenchymal transition (EMT)-related markers. Matrigel invasion chamber assay was performed to evaluate the TNBC cells invasion patterns under treatments of either NVP-TAE226 or NVP-BEZ235 alone or the two drugs in combination. Spheroid migration assay will also be used to assess combination effect on the metastatic nature of TNBC cells. Results: The combined IGF1R/FAK inhibition with NVP-TAE226 and PI3K/mTOR inhibition with NVP-BEZ235 resulted in significantly greater cytotoxicity than either single agent alone in MDA-MB231 and BT549 cell lines (P<0.05). The combination of IGF1R/FAK and PI3K/mTOR inhibition suppressed the PI3K/Akt and MEK/ERK signaling cascades, reduced FAK and ZEB1 activity and significantly decreased the cell invasion for TNBC cell lines (p<0.05). Our data indicated that the combination treatment targeting both PI3K/Akt pathway and EMT related protein molecules (IGF1R/FAK) lead to greater cytotoxic effect and suppression of EMT and invasion. Conclusion: These results suggest that the combined inhibition of IGF1R/FAK and PI3K/mTOR may be an effective strategy for TNBC and warrant further investigation in in vivo animal studies. Citation Format: LaTonia D Taliaferro-Smith, Tongrui Liu, Tiffanie Y Alcaide, Tanisha Z McGlothen, Ruth M O'Regan. Combination of IGF1R/FAK inhibition and PI3K/mTOR inhibition in triple-negative breast cancers [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-07-07.