Selective tumor killing based on specific DNA-damage response deficiencies

Abstract

Organisms constantly undergo various stresses within their life span, which can damage their DNA. In order to maintain genomic stability and counteract the development of unwanted genomic mutations, organisms have evolved a DNA-damage response (DDR) to protect their genome. Due to the critical roles played by DDR in genomic stability, its defects can lead to cellular transformation and potentially tumorigenesis. Consequently, this also provides the opportunity to specifically target tumor cells due to a weakened ability to tolerate genotoxic stresses. In this lies a treatment strategy in which the inhibition of remaining DDR pathways can hyper-sensitize tumors to chemotherapeutic agents while minimizing deleterious effects to healthy cells. Therefore it is important to understand the genotypic background of specific tumors to determine which DDR pathways remain and can be targeted for inhibition. Tumor therapies based on the DDR are ideal not only as a means of increasing the effectiveness of current chemotherapies but also as a means to selectively target tumor cells while leaving healthy cells unharmed. Thus, targeting DDR components as a means of increasing effectiveness and discrimination of current chemotherapeutic tumor treatments is currently the focus of many studies and clinical trials.

Keywords:

• DNA-damage response
• tumor
• chemotherapy
• synergism

Acknowledgments

We wish to thank Michelle Hanna for proofreading the manuscript and other laboratory members for helpful discussion. This work was supported by Natural Sciences and Engineering Research Council of Canada Discovery Grant No. 138338-2009 to W.X., M.B. is a recipient of the Graduate Scholarship from the College of Medicine, University of Saskatchewan.

Figures and Tables

Figure 1 ATM/ATR DNA-damage response pathway. Open boxes indicate damage signals; gray boxes indicate the genetic components; filled boxes represent the downstream consequences of the response pathway. Arrows indicate the ability of one component of the pathway to lead to the activation of a subsequent component.

Table 1 Inhibitors of the DDR undergoing clinical trials