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Curr Med Chem. 2018 Jan 16. doi: 10.2174/0929867325666180117102233. [Epub ahead of print]

Breaking the DNA damage response via serine/threonine kinase inhibitors to improve cancer treatment.

Author information

1
Department of Clinical Chemistry and Biochemistry, Military-Medical Faculty, Medical University of Lodz, Lodz. Poland.
2
Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston. United States.

Abstract

Multiple, both endogenous and exogenous, sources may induce DNA damage and DNA replication stress. Cells have developed DNA damage response (DDR) signaling pathways to maintain genomic stability and effectively detect and repair DNA lesions. Serine/threonine kinases such as Ataxia-telangiectasia mutated (ATM) and Ataxia-telangiectasia and Rad3-Related (ATR) are the major regulators of DDR, since after sensing stalled DNA replication forks, DNA double- or single-strand breaks, may directly phosphorylate and activate their downstream targets, that play a key role in DNA repair, cell cycle arrest and apoptotic cell death. Interestingly, key components of DDR signaling networks may constitute an attractive targets for anti-cancer therapy through two distinct potential approaches: as a chemo- and radiosensitizers to enhance the effectiveness of currently used genotoxic treatment or as a single agents to exploit defects in DDR in cancer cells via synthetic lethal approach. Moreover, the newest data reported that serine/threonine protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is also closely associated with cancer development and progression. Thereby, utilization of small-molecule, serine/threonine kinase inhibitors may provide a novel, groundbreaking, anti-cancer treatment strategy. Currently, a range of potent, highly-selective toward ATM, ATR and PERK inhibitors has been discovered, but after foregoing study, additional investigations are necessary for their future clinical use.

KEYWORDS:

ATM; ATR; Cancer; DNA damage response; PERK; cancer treatment. ; kinase inhibitors

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