title: Radiosensitizing effect of lapatinib in human epidermal growth factor receptor 2-positive breast cancer cells.
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.
authors.affiliation: Department of Radiation Oncology, Graduate School of Medicine, Seoul National University, Seoul, Republic of Korea.
authors.forename: Tosol
authors.initials: T
authors.lastname: Yu
authors.affiliation: Medical Science Research Institute, Seoul National University Bundang Hospital, Seongnam, Seoul, Republic of Korea.
authors.forename: Bong Jun
authors.initials: BJ
authors.lastname: Cho
authors.affiliation: Department of Radiation Oncology, Graduate School of Medicine, Seoul National University, Seoul, Republic of Korea.
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Choi
authors.affiliation: Department of Radiation Oncology, Graduate School of Medicine, Seoul National University, Seoul, Republic of Korea.|Medical Science Research Institute, Seoul National University Bundang Hospital, Seongnam, Seoul, Republic of Korea.
authors.forename: Ji Min
authors.initials: JM
authors.lastname: Park
authors.affiliation: Medical Science Research Institute, Seoul National University Bundang Hospital, Seongnam, Seoul, Republic of Korea.
authors.forename: Dan Hyo
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Department of Radiation Oncology, Graduate School of Medicine, Seoul National University, Seoul, Republic of Korea.|Medical Science Research Institute, Seoul National University Bundang Hospital, Seongnam, Seoul, Republic of Korea.|Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Republic of Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.|Institute of Radiation Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: In Ah
authors.initials: IA
authors.lastname: Kim
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D051747:DNA-Activated Protein Kinase / Q000378:metabolism; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D000077341:Lapatinib; D061986:MCF-7 Cells; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D011799:Quinazolines / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D051747:DNA-Activated Protein Kinase; D000077341:Lapatinib; D009687:Nuclear Proteins; D011799:Quinazolines; D011838:Radiation-Sensitizing Agents; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human; C497263:PRKDC protein, human
keywords: breast cancer; human epidermal growth factor receptor 2; lapatinib; radiotherapy