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Recent advances in cancer therapy targeting proteins involved in DNA double-strand break repair

Bolderson, Emma, Richard, Derek J., Zhou, Bin-Bing S., & Khanna, Kum Kum (2009) Recent advances in cancer therapy targeting proteins involved in DNA double-strand break repair. Clinical Cancer Research, 15(20), pp. 6314-6320.

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Abstract

Damage to genetic material represents a persistent and ubiquitous threat to genomic stability. Once DNA damage is detected, a multifaceted signaling network is activated that halts the cell cycle, initiates repair, and in some instances induces apoptotic cell death. In this article, we will review DNA damage surveillance networks, which maintain the stability of our genome, and discuss the efforts underway to identify chemotherapeutic compounds targeting the core components of DNA double-strand breaks (DSB) response pathway. The majority of tumor cells have defects in maintaining genomic stability owing to the loss of an appropriate response to DNA damage. New anticancer agents are exploiting this vulnerability of cancer cells to enhance therapeutic indexes, with limited normal tissue toxicity. Recently inhibitors of the checkpoint kinases Chk1 and Chk2 have been shown to sensitize tumor cells to DNA damaging agents. In addition, the treatment of BRCA1- or BRCA2-deficient tumor cells with poly(ADP-ribose) polymerase (PARP) inhibitors also leads to specific tumor killing. Due to the numerous roles of p53 in genomic stability and its defects in many human cancers, therapeutic agents that restore p53 activity in tumors are the subject of multiple clinical trials. In this article we highlight the proteins mentioned above and catalog several additional players in the DNA damage response pathway, including ATM, DNA-PK, and the MRN complex, which might be amenable to pharmacological interventions and lead to new approaches to sensitize cancer cells to radio- and chemotherapy. The challenge is how to identify those patients most receptive to these treatments.

Impact and interest:

99 citations in Scopus
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93 citations in Web of Science®

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ID Code: 40609
Item Type: Journal Article
Keywords: genomic stability, genetic material, apoptotic cell death
DOI: 10.1158/1078-0432.CCR-09-0096
ISSN: 1078-0432
Subjects: Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > ONCOLOGY AND CARCINOGENESIS (111200)
Divisions: Past > QUT Faculties & Divisions > Faculty of Science and Technology
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2009 American Association for Cancer Research
Deposited On: 09 Mar 2011 13:50
Last Modified: 01 Mar 2012 00:31

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