Abstract
BackgroundHER2-positive breast cancers exhibit high rates of innate and acquired resistance to trastuzumab (TZ), a HER2-directed antibody used as a first line treatment for this disease. TZ resistance may in part be mediated by frequent co-expression of EGFR and by sustained activation of the mammalian target of rapamycin (mTOR) pathway. Here, we assessed feasibility of combining the EGFR inhibitor gefitinib and the mTOR inhibitor everolimus (RAD001) for treating HER2 overexpressing breast cancers with different sensitivity to TZ.MethodsThe gefitinib and RAD001 combination was broadly evaluated in TZ sensitive (SKBR3 and MCF7-HER2) and TZ resistant (JIMT-1) breast cancer models. The effects on cell growth were measured in cell based assays using the fixed molar ratio design and the median effect principle. In vivo studies were performed in Rag2M mice bearing established tumors. Analysis of cell cycle, changes in targeted signaling pathways and tumor characteristics were conducted to assess gefitinib and RAD001 interactions.ResultsThe gefitinib and RAD001 combination inhibited cell growth in vitro in a synergistic fashion as defined by the Chou and Talalay median effect principle and increased tumor xenograft growth delay. The improvement in therapeutic efficacy by the combination was associated in vitro with cell line dependent increases in cytotoxicity and cytostasis while treatment in vivo promoted cytostasis. The most striking and consistent therapeutic effect of the combination was increased inhibition of the mTOR pathway (in vitro and in vivo) and EGFR signaling in vivo relative to the single drugs.ConclusionsThe gefitinib and RAD001 combination provides effective control over growth of HER2 overexpressing cells and tumors irrespective of the TZ sensitivity status.
Highlights
HER2-positive breast cancers exhibit high rates of innate and acquired resistance to trastuzumab (TZ), a HER2-directed antibody used as a first line treatment for this disease
The expression of HER-3 protein was highest in MCF7-HER2 and relatively low in SKBR3 and JIMT-1 cells and P-AKT was constitutively expressed in all three cell lines (Figure 1A)
The IC50 values for gefitinib after 72 h treatment were 4.3 ± 1.2 μM in SKBR3 cells and > 10 μM in JIMT-1 and MCF7-HER2 cells; after 144 h the IC50 values were 1.6 ± 1, 5 ± 0.5 and > 10 μM respectively in SKBR3, JIMT-1 and MCF7-HER2 cells. These results showed that SKBR3 cells were sensitive, JIMT-1 cells were moderately resistant and MCF7-HER2 cells were exceptionally resistant to gefitinib
Summary
HER2-positive breast cancers exhibit high rates of innate and acquired resistance to trastuzumab (TZ), a HER2-directed antibody used as a first line treatment for this disease. Co-expression of EGFR and HER2 in breast cancer cell lines has been shown to induce drug resistance, including resistance to TZ [17,18], and has been correlated with a negative prognosis for breast cancer patients [1,11]. These data suggested that EGFR constitutes an important therapeutic target in breast cancers and have prompted investigators to consider gefitinib (ZD1839, Iressa®), a reversible small molecule inhibitor of the EGFR tyrosine kinase, for treatment of HER2 overexpressing and EGFR coexpressing breast malignancies [19]
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