Radiosensitizing effect of lapatinib in human epidermal growth factor receptor 2-positive breast cancer cells
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Tosol Yu1,*, Bong Jun Cho2,*, Eun Jung Choi1,*, Ji Min Park1,2, Dan Hyo Kim2, In Ah Kim,1,2,3,4,5
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
*These authors have contributed equally to this work
In Ah Kim, email: email@example.com
Keywords: breast cancer, human epidermal growth factor receptor 2, radiotherapy, lapatinib
Received: February 23, 2016 Accepted: September 25, 2016 Published: October 12, 2016
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.
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