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Research Articles: Therapeutics, Targets, and Development

Loss of ataxia telangiectasia mutated– and Rad3-related function potentiates the effects of chemotherapeutic drugs on cancer cell survival

Department of Radiation Oncology and Molecular Radiation Sciences and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland

Requests for reprints: Fred Bunz, Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, CRB2, Room 453, 1550 Orleans Street, Baltimore, MD 21231. Phone: 410-502-7941; Fax: 410-502-7234. E-mail: fbunz{at}jhmi.edu.

Abstract

The diverse responses of human cells to various forms of DNA damage are controlled by a complex network of signaling proteins. There has been considerable interest in the components of this signaling apparatus as potential targets for new forms of anticancer therapy. In this report, we examine the contributions of an upstream signaling molecule, the ataxia telangiectasia mutated– and Rad3-related (ATR) protein kinase, to the resistance of cancer cells to DNA-damaging agents that are commonly used as anticancer therapeutics. Loss of ATR function in knock-in cancer cells strikingly enhanced the effects of several of the most commonly used therapeutic compounds, impeding the progression of the cell cycle and reducing long-term cancer cell survival. Loss of ATR function potentiated the toxicity of alkylating agents most strikingly, antimetabolites moderately, and double-strand break–inducing agents to a lesser extent. These results suggest that specific inhibition of ATR activity will be a valid strategy to increase the effectiveness of currently used modes of therapy. [Mol Cancer Ther 2007;6(4):1406–13]

Grant support: Flight Attendant Medical Research Institute and National Cancer Institute grant CA104253 (F. Bunz) and Ruth L. Kirschstein National Research Service Award CA119724 (D. Wilsker).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 11/ 3/06; revised 1/ 3/07; accepted 2/20/07.

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