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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. 

Author information​

Yu T1, Cho BJ2, Choi EJ1, Park JM1,2, Kim DH2, Kim IA1,2,3,4,5.

1Department of Radiation Oncology, Graduate School of Medicine, Seoul National University, Seoul, Republic of Korea.

2Medical Science Research Institute, Seoul National University Bundang Hospital, Seongnam, Seoul, Republic of Korea.

3Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Republic of Korea.

4Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.

5Institute of Radiation Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.