Division of Molecular Radiation Biology, Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas 75390, TX, USA.
Semin Radiat Oncol. 2010 Oct;20(4):250-7. doi: 10.1016/j.semradonc.2010.05.002.
DNA double-strand breaks (DSBs) are the most lethal type of DNA damage induced by ionizing radiation or chemotherapeutic drugs used to eradicate cancer cells. The ability of cancer cells to effectively repair DSBs significantly influences the outcome of therapeutic regimens. Therefore, a new and important area of clinical cancer research is the development of DNA repair inhibitors that can be used as radio- or chemosensitizers. Nonhomologous end joining (NHEJ) is the predominant pathway for the repair of radiation-induced DSBs. A series of recent reports indicates that the epidermal growth factor receptor (EGFR) or its downstream components may modulate NHEJ through direct interaction with the DNA repair enzyme, DNA-dependent protein kinase. Because EGFR is overexpressed or activated in many cancers, these findings provide a compelling rationale for combining radiotherapy with therapies that block EGFR or its downstream signaling components. In this review, we delineate how these novel connections between a cell-surface receptor (EGFR) and a predominantly nuclear event (NHEJ) provide vulnerable nodes that can be selectively targeted to improve cancer therapy.
DNA 双链断裂（DSBs）是由电离辐射或用于消灭癌细胞的化疗药物引起的最致命的 DNA 损伤类型。癌细胞有效修复 DSB 的能力显著影响治疗方案的结果。因此，开发可作为放射增敏剂或化疗增敏剂的 DNA 修复抑制剂是临床癌症研究的一个新的重要领域。非同源末端连接（NHEJ）是修复辐射诱导的 DSB 的主要途径。最近的一系列报告表明，表皮生长因子受体（EGFR）或其下游成分可能通过与 DNA 修复酶 DNA 依赖性蛋白激酶的直接相互作用来调节 NHEJ。由于 EGFR 在许多癌症中过度表达或激活，这些发现为将放射治疗与阻断 EGFR 或其下游信号传导成分的治疗相结合提供了强有力的理由。在这篇综述中，我们阐述了细胞表面受体（EGFR）和主要核事件（NHEJ）之间的这些新联系如何为可选择性靶向以改善癌症治疗的脆弱节点提供了依据。
