Peng Guang, Lin Shiaw-Yih
Guang Peng, Shiaw-Yih Lin, Department of Systems Biology, Unit 950, The University of Texas MD Anderson Cancer Center, South Campus Research Building II, 7435 Fannin, Houston, TX 77054, United States.
World J Clin Oncol. 2011 Feb 10;2(2):73-9. doi: 10.5306/wjco.v2.i2.73.
Genomic instability is a characteristic of cancer cells. In order to maintain genomic integrity, cells have evolved a complex DNA repair system to detect, signal and repair a diversity of DNA lesions. Homologous recombination (HR)-mediated DNA repair represents an error-free repair mechanism to maintain genomic integrity and ensure high-fidelity transmission of genetic information. Deficiencies in HR repair are of tremendous importance in the etiology of human cancers and at the same time offer great opportunities for designing targeted therapeutic strategies. The increase in the number of proteins identified as being involved in HR repair has dramatically shifted our concept of the proteins involved in this process: traditionally viewed as existing in a linear and simple pathway, today they are viewed as existing in a dynamic and interconnected network. Moreover, exploration of the targets within this network that can be modulated by small molecule drugs has led to the discovery of many effective kinase inhibitors, such as ATM, ATR, DNA-PK, CHK1, and CHK2 inhibitors. In preclinical studies, these inhibitors have been shown to sensitize cancer cells to chemotherapy and radiation therapy. The most exciting discovery in the field of HR repair is the identification of the synthetic lethality relationship between poly (ADP-ribose) polymerase (PARP) inhibitors and HR deficiency. The promises of clinical applications of PARP inhibitors and the concept of synthetic lethality also bring challenges into focus. Future research directions in the area of HR repair include determining how to identify the patients most likely to benefit from PARP inhibitors and developing strategies to overcome resistance to PARP inhibitors.
基因组不稳定是癌细胞的一个特征。为了维持基因组完整性，细胞进化出了一个复杂的DNA修复系统来检测、发出信号并修复多种DNA损伤。同源重组（HR）介导的DNA修复是一种无差错的修复机制，可维持基因组完整性并确保遗传信息的高保真传递。HR修复缺陷在人类癌症病因学中极为重要，同时也为设计靶向治疗策略提供了巨大机遇。被确定参与HR修复的蛋白质数量的增加，极大地改变了我们对参与这一过程的蛋白质的概念：传统上认为它们以线性和简单的途径存在，如今则认为它们存在于一个动态且相互关联的网络中。此外，对该网络中可被小分子药物调节的靶点的探索，导致发现了许多有效的激酶抑制剂，如ATM、ATR、DNA-PK、CHK1和CHK2抑制剂。在临床前研究中，这些抑制剂已被证明可使癌细胞对化疗和放疗敏感。HR修复领域最令人兴奋的发现是确定了聚（ADP-核糖）聚合酶（PARP）抑制剂与HR缺陷之间的合成致死关系。PARP抑制剂临床应用的前景以及合成致死的概念也使挑战成为焦点。HR修复领域未来的研究方向包括确定如何识别最有可能从PARP抑制剂中获益的患者，以及制定克服对PARP抑制剂耐药性的策略。
