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World J Clin Oncol. 2011 Feb 10;2(2):73-9. doi: 10.5306/wjco.v2.i2.73.

Exploiting the homologous recombination DNA repair network for targeted cancer therapy.

Author information

  • 1Guang 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.

Abstract

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.

KEYWORDS:

DNA repair; Genomic instability; Homologous-recombination-mediated DNA repair; Poly polymerase inhibitors; Synthetic lethality

PMID:
21603316
[PubMed]
PMCID:
PMC3095467
Free PMC Article
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