Radiosensitizing effect of lapatinib in human epidermal growth factor receptor 2-positive breast cancer cells

Abstract

// Tosol Yu 1, * , Bong Jun Cho 2, * , Eun Jung Choi 1, * , Ji Min Park 1, 2 , Dan Hyo Kim 2 , In Ah Kim, 1, 2, 3, 4, 5 1 Department of Radiation Oncology, Graduate School of Medicine, Seoul National University, Seoul, Republic of Korea 2 Medical Science Research Institute, Seoul National University Bundang Hospital, Seongnam, Seoul, Republic of Korea 3 Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Republic of Korea 4 Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea 5 Institute of Radiation Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea * These authors have contributed equally to this work Correspondence to: In Ah Kim, email: inah228@snu.ac.kr Keywords: breast cancer, human epidermal growth factor receptor 2, radiotherapy, lapatinib Received: February 23, 2016     Accepted: September 25, 2016     Published: October 12, 2016 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.