Effect of afatinib alone and in combination with trastuzumab in HER2-positive breast cancer cell lines.

Abstract

632 Background: Trastuzumab and lapatinib have been shown to significantly improve the prognosis for HER2 positive breast cancer patients. However, resistance is a significant clinical problem. The aim of this study is to assess the activity of afatinib, an irreversible pan-HER tyrosine kinase inhibitor, in HER2 overexpressing breast cancer cell lines, including trastuzumab and/or lapatinib resistant cells. Methods: Using proliferation assays, the effect of afatinib was assessed alone and in combination with trastuzumab in HER2 positive cell lines. The effect of afatinib on HER2, Erk and Akt was determined by immunoblotting. Results: The eight HER2 positive breast cancer cell lines tested, including trastuzumab and/or lapatinib resistant cells, responded to afatinib with IC50values ranging from 5 to 80 nM. The combination of afatinib and trastuzumab was additive in four trastuzumab sensitive cell lines and one model of acquired trastuzumab resistant HER2 positive breast cancer. In the remaining three trastuzumab and/or lapatinib resistant cell lines, combined treatment with trastuzumab and afatinib showed no enhancement compared to afatinib alone. Finally, afatinib decreased the phosphorylation of HER2 and Erk in all cell lines tested. Conclusions: Our results suggest that afatinib has activity in HER2 positive breast cancer, including trastuzumab and/or lapatinib resistant breast cancer. We also demonstrate that afatinib in combination with trastuzumab may be more effective than either agent alone in trastuzumab sensitive breast cancer. [Table: see text]