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Trends Genet. 2014 Aug;30(8):326-39. doi: 10.1016/j.tig.2014.06.003. Epub 2014 Jul 10.

Cancer-specific defects in DNA repair pathways as targets for personalized therapeutic approaches.

Author information

1
Department of Internal Medicine, University Hospital of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, 50674 Cologne, Germany. Electronic address: fdietlei@smail.uni-koeln.de.
2
Department of Internal Medicine, University Hospital of Cologne, 50931 Cologne, Germany.
3
Department of Internal Medicine, University Hospital of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, 50674 Cologne, Germany. Electronic address: christian.reinhardt@uk-koeln.de.

Abstract

Defects in DNA repair pathways enable cancer cells to accumulate genomic alterations that contribute to their aggressive phenotype. However, tumors rely on residual DNA repair capacities to survive the damage induced by genotoxic stress. This dichotomy might explain why only isolated DNA repair pathways are inactivated in cancer cells. Accordingly, synergism has been observed between DNA-damaging drugs and targeted inhibitors of DNA repair. DNA repair pathways are generally thought of as mutually exclusive mechanistic units handling different types of lesions in distinct cell cycle phases. Recent preclinical studies, however, provide strong evidence that multifunctional DNA repair hubs, which are involved in multiple conventional DNA repair pathways, are frequently altered in cancer. We therefore propose that targeted anticancer therapies should not only exploit synthetic lethal interactions between two single genes but also consider alterations in DNA repair hubs. Such a network-based approach considerably increases the opportunities for targeting DNA repair-defective tumors.

PMID:
25017190
DOI:
10.1016/j.tig.2014.06.003
[Indexed for MEDLINE]

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