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Abstract
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-EGFR, p-AKT, and p-ERK. 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 DNAdependent 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 results suggest that lapatinib can potentiate radiation-induced cell death in HER2-overexpressing breast cancer cells and may increase the efficacy of radiotherapy. Based on these findings, RTOG1119 study which is a phase II randomized study for lapatinib combined with radiation therapy in patients with brain metastases from HER2-positive breast cancer is ongoing (NCT 01622868). Citation Format: Tosol Yu, Bong Jun Cho, Eun Jung Choi, Ji Min Park, Dan Hyo Kim, In Ah Kim. Radiosensitizing effect of lapatinib in HER2-overexpressing breast cancer cells: scientific rationale for RTOG1119 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5184. doi:10.1158/1538-7445.AM2017-5184
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