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Abstract
Trastuzumab has been widely used for the treatment of human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer, however, it cannot easily cross the blood-brain barrier (BBB) and is known to increase the incidence of brain metastases. In contrast, lapatinib has a low molecular weight and can cross the BBB and it could be useful to treat brain metastases in patients with HER2-positive breast cancer.To explore the impact of lapatinib on radiation response, we conducted an in vitro experiment using SKBR3 and BT474 breast carcinoma cells exhibiting HER2/neu amplification. Lapatinib down-regulated phosphorylated (p)-HER2, p-epidermal growth factor receptor, p-AKT, and p-extracellular signal-regulated kinase. Pretreatment of lapatinib increased the radiosensitivity of SKBR3 (sensitizer enhancement ratio [SER]: 1.21 at a surviving fraction of 0.5) and BT474 (SER: 1.26 at a surviving fraction of 0.5) cells and hindered the repair of DNA damage, as suggested by the prolongation of radiation-induced γH2AX foci and the down-regulation of phosphorylated DNA-dependent protein kinase, catalytic subunit (p-DNAPKcs). Increases in radiation-induced apoptosis and senescence were suggested to be the major modes of cell death induced by the combination of lapatinib and radiation. Furthermore, lapatinib did not radiosensitize a HER2- negative breast cancer cell line or normal human astrocytes.These findings suggest that lapatinib can potentiate radiation-induced cell death in HER2-overexpressing breast cancer cells and may increase the efficacy of radiotherapy. A phase II clinical trial using lapatinib concurrently with whole-brain radiation therapy (WBRT) is currently being conducted.
Highlights
The human epidermal growth factor receptor 2 (HER2) is overexpressed in about 20 to 30% of breast carcinomas and is associated with aggressive clinical course [1]
To explore the impact of lapatinib on radiation response, SKBR3 and BT474 breast carcinoma cells exhibiting HER2/neu amplification were treated with dimethyl sulfoxide (DMSO) or 5 μM lapatinib
We investigated the radiosensitizing effect of lapatinib in HER2+, HER2- breast cancer cells and normal human astrocytes
Summary
The human epidermal growth factor receptor 2 (HER2) is overexpressed in about 20 to 30% of breast carcinomas and is associated with aggressive clinical course [1]. The introduction of trastuzumab, an anti-HER2 monoclonal antibody, has dramatically improved the survival of HER2-positive patients [2,3,4,5]. The incidence of brain metastasis is significantly increased in HER2-positive breast cancer after trastuzumab treatment. This may be due to the fact that trastuzumab enhances systemic control and prolongs survival, clinically disclosing brain metastasis [6]. Despite receiving trastuzumab-based therapy, approximately 30% of patients www.impactjournals.com/oncotarget with HER2-positive metastatic breast cancer develop brain metastasis, and intracranial disease progression, rather than extracranial disease, is the main cause of death in those patients [7,8,9,10]
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