Universität zu Köln

Dietlein, Felix and Reinhardt, H. Christian (2014). Molecular Pathways: Exploiting Tumor-Specific Molecular Defects in DNA Repair Pathways for Precision Cancer Therapy. Clin. Cancer Res., 20 (23). S. 5882 - 5888. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1557-3265

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Abstract

Disabling mutations in genome maintenance and DNA repair pathways are frequently observed in cancer. These DNA repair defects represent genetic aberrations that are specific to cancer cells and not present in healthy tissues. It is thought that these molecular defects produce a mutator phenotype, which allows incipient cancer cells to accumulate additional cancer-promoting mutations. In recent years, our molecular understanding of DNA double-strand break (DSB) repair mechanisms has led to the development of targeted therapeutic approaches to selectively eradicate cancer cells that display defects in homologous recombination-mediated DNA DSB repair. These regimens for the treatment of homologous recombination-defective tumors predominantly aim at pharmacologically repressing the activity of PARP1, which is crucial for base excision repair, or to inhibit the nonhomologous end joining kinase DNA-PKcs ( DNA-dependent protein kinase, catalytic subunit). Normal tissue can bypass PARP1- or DNA-PKcs inhibitor-induced genotoxic lesions via homologous recombination-mediated DNA DSB repair. In contrast, homologous recombination-defective cancer cells are unable to properly repair DNA DSBs, in the presence of PARP1 or DNA-PKcs inhibitors, ultimately leading to apoptotic cancer cell death. (C) 2014 AACR.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Dietlein, Felix UNSPECIFIED UNSPECIFIED UNSPECIFIED Reinhardt, H. Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-422415
DOI:	10.1158/1078-0432.CCR-14-1165
Journal or Publication Title:	Clin. Cancer Res.
Volume:	20
Number:	23
Page Range:	S. 5882 - 5888
Date:	2014
Publisher:	AMER ASSOC CANCER RESEARCH
Place of Publication:	PHILADELPHIA
ISSN:	1557-3265
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language IDENTIFIES RECURRENT MUTATIONS; SYNTHETIC LETHAL INTERACTION; CHRONIC LYMPHOCYTIC-LEUKEMIA; BRCA MUTANT-CELLS; POLY(ADP-RIBOSE) POLYMERASE; HOMOLOGOUS RECOMBINATION; PANCREATIC-CANCER; DAMAGE RESPONSE; FANCONI-ANEMIA; OVARIAN-CANCER Multiple languages Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/42241