title: Radiosensitization of brain metastasis by targeting c-MET.
abstract: Radiotherapy is the most widely used therapeutic modality in brain metastasis; however, it only provides palliation due to inevitable tumor recurrence. Resistance of tumor cells to ionizing radiation is a major cause of treatment failure. A critical unmet need in oncology is to develop rationale driven approaches that can enhance the efficacy of radiotherapy against metastatic tumor. Utilizing in vivo orthotopic primary tumor and brain metastasis models that recapitulate clinical situation of the patients with metastatic breast cancer, we investigated a molecular mechanism through which metastatic tumor cells acquire resistance to radiation. Recent studies have demonstrated that the hepatocyte growth factor (HGF)-c-Met pathway is essential for the pathologic development and progression of many human cancers such as proliferation, invasion and resistance to anticancer therapies. In this study, c-Met signaling activity as well as total c-Met expression was significantly upregulated in both breast cancer cell lines irradiated in vitro and ex vivo radio-resistant cells derived from breast cancer brain metastatic xenografts. To interrogate the role of c-Met signaling in radioresistance of brain metastasis, we evaluated the effects on tumor cell viability, clonogenicity, sensitivity to radiation, and in vitro/in vivo tumor growth after targeting c-Met by small-hairpin RNA (shRNA) or small-molecule kinase inhibitor (PF-2341066). Although c-Met silencing or radiation alone demonstrated a modest decrease in clonogenic growth of parental breast cancers and brain metastatic derivatives, combination of two modalities showed synergistic antitumor effects resulting in significant prolongation of overall survival in tumor-bearing mice. Taken together, optimizing c-Met targeting in combination with radiation is critical to enhance the effectiveness of radiotherapy in the treatments of brain metastasis.
authors: Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors: Heekyoung
authors: H
authors: Yang
authors: Hye Won
authors: HW
authors: Lee
authors: Yonghyun
authors: Y
authors: Kim
authors: Yeri
authors: Y
authors: Lee
authors: Yeon-Sook
authors: YS
authors: Choi
authors: Kang Ho
authors: KH
authors: Kim
authors: Juyoun
authors: J
authors: Jin
authors: Jeongwu
authors: J
authors: Lee
authors: Kyeung Min
authors: KM
authors: Joo
authors: Do-Hyun
authors: DH
authors: Nam
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001932:Brain Neoplasms / Q000532:radiotherapy* / Q000556:secondary*; D001943:Breast Neoplasms / Q000473:pathology*; D059248:Chemoradiotherapy / Q000379:methods*; D000077547:Crizotinib; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000528:radiation effects; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D010880:Piperidines / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011720:Pyrazoles; D011725:Pyridines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D011836:Radiation Tolerance / Q000187:drug effects*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects* / Q000528:radiation effects; D014407:Tumor Cells, Cultured
chemical_list: D010880:Piperidines; D011720:Pyrazoles; D011725:Pyridines; D034741:RNA, Small Interfering; D000077547:Crizotinib; D019859:Proto-Oncogene Proteins c-met