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

• Type of Material: Article
• Authors: Tongrui Liu, Emory University; Rami Yacoub, Emory University; LaTonia Taliaferro-Smith, Emory University; Shi-Yong Sun, Emory University; Tisheeka R. Graham, Emory University; Ryan Dolan, Emory University; Christine Lobo, Emory University; Mourad Tighiouart, Emory University; Lily Yang, Emory University; Amy Adams, Emory University; Ruth O'Regan, Emory University
• Language: English
• Date: 2011-08-01
• Publisher: American Association for Cancer Research
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: ©2011 American Association for Cancer Research.
• Final Published Version (URL): http://dx.doi.org/10.1158/1535-7163.MCT-10-0925
• Title of Journal or Parent Work: Molecular Cancer Therapeutics
• ISSN: 1535-7163
• Volume: 10
• Issue: 8
• Start Page: 1460
• End Page: 1469
• Grant/Funding Information: This study was supported by Wilbur and Hilda Glenn Foundation and Georgia Cancer Coalition (both to R. O’Regan).
• Keywords: Life Sciences & Biomedicine; EIF4E; AKT; GROWTH; SURVIVAL; EFFICACY; ONCOLOGY; ACTIVATION; PACLITAXEL; Oncology; MAMMALIAN TARGET; INHIBITION; Science & Technology; REDUCTION
• Research Categories: Health Sciences, Medicine and Surgery; Biology, Biostatistics; Health Sciences, Oncology

Abstract

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 with metastatic 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 compared with 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 correlated with a decrease in activated eukaryotic translation initiation factor (eIF4E). These results suggest that mTOR inhibitors could sensitize a subset of triple-negative breast cancers to EGFR inhibitors. Given the paucity of effective targeted agents in triple-negative breast cancers, these results warrant further evaluation.