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

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 effects were 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.

Abrogating phosphorylation of eIF4B is required for EGFR and mTOR inhibitor synergy in triple-negative breast cancer

“…[4] (See Online Resource 1 for demonstration of EGFR kinase inhibition in TNBC with gefitinib). To identify potential mechanisms of resistance in TNBC cells to EGFR inhibitors we treated the TNBC cell line BT20 with 0.5 μM gefitinib (a concentration previously shown to be selective for EGFR) or DMSO (a vehicle control) and performed phospho-mass spectrometry.…”

“…[1,3,4] In addition to breast cancer, EGFR is overexpressed in colon and non-small cell lung carcinoma where inhibitory antibodies and small molecule tyrosine kinase inhibitors are used efficaciously in the clinic. [5] Unfortunately, the use of the EGFR inhibitor cetuximab in TNBC has been ineffective.…”

“…[6] One proposed mechanism for this intrinsic resistance to EGFR inhibitors in TNBC is crosstalk between EGFR and other signaling proteins. [4,7,5,2] Specifically, crosstalk between c-Met, c-Src, IGF-IR, HER2, and HER3 signaling with EGFR activation has been shown to abrogate the efficacy of monotherapy tyrosine kinase inhibitors and promote resistance to EGFR targeted therapies. [5]…”

Preclinical Evaluation of a Novel Orally Available SRC/Raf/VEGFR2 Inhibitor, SKLB646, in the Treatment of Triple-Negative Breast Cancer

“…A significant risk of developing metastases in TNBC is one of main causes responsible for a poor prognosis (43). For example, TNBC has been demonstrated to be much more easier to metastasize to viscera (44), particularly to the lungs, than other subtypes of breast cancer (45).…”

Molecular Pathways: PI3K Pathway Targets in Triple-Negative Breast Cancers

“…However, even resistance to this combination was observed in some TNBC xenografts, which could only be overcome with the addition of the MAP-ERK kinase inhibitor AZD6244 (54). Similar preclinical TNBC models have also shown the synergistic effect of combining EGF receptor (EGFR) and mTOR inhibition (55). These observations still need to be tested in the clinical setting.…”