Preclinical Development Combinatorial Effects of Lapatinib and Rapamycin in Triple-Negative Breast Cancer Cells

Triple-negative breast cancers, which lack estrogen receptor, progesterone receptor, and HER2/neu overexpression, account for approximately 15% of breast cancers, but occur more commonly in African Americans. The poor survival outcomes seen with triple-negative breast cancers patients are, in part, due to a lack of therapeutic targets. Epidermal growth factor receptor (EGFR) is overexpressed in 50% of triple-negative breast cancers, but EGFR inhibitors have not been effective in patients withmetastatic breast cancers. However,mTOR inhibition has been shown to reverse resistance to EGFR inhibitors. We examined the combination effects of mTOR inhibition with EGFR inhibition in triple-negative breast cancer in vitro and in vivo. The combination of EGFR inhibition by using lapatinib and mTOR inhibition with rapamycin resulted in significantly greater cytotoxicity than the single agents alone and these effectswere synergistic in vitro. The combination of rapamycin and lapatinib significantly decreased growth of triple-negative breast cancers in vivo comparedwith either agent alone. EGFR inhibition abrogated the expression of rapamycin-induced activated Akt in triple-negative breast cancer cells in vitro. The combination of EGFR and mTOR inhibition resulted in increased apoptosis in some, but not all, triple-negative cell lines, and these apoptotic effects correlatedwith a decrease in activated eukaryotic translation initiation factor (eIF4E). These results suggest thatmTOR inhibitors could sensitize a subset of triplenegativebreast cancers toEGFR inhibitors.Given thepaucity of effective targeted agents in triple-negativebreast cancers, these results warrant further evaluation. Mol Cancer Ther; 10(8); 1460–9. 2011 AACR.