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DNA Damage Detection and Repair Pathways—Recent Advances with Inhibitors of Checkpoint Kinases in Cancer Therapy

Authors' Affiliation: AstraZeneca R&D Boston, Waltham, Massachusetts

Requests for reprints: Susan Ashwell, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham MA 02451. Phone: 1-781-839-4857; Fax: 1-781-839-4200; E-mail: susan.ashwell{at}astrazeneca.com.

Abstract

Insights from cell cycle research have led to the hypothesis that tumors may be selectivity sensitized to DNA-damaging agents, resulting in improved antitumor activity and a wider therapeutic margin. The theory relies primarily on the observation that the majority of tumors are deficient in the G₁-DNA damage checkpoint pathway, resulting in reliance on S and G₂ phase checkpoints for DNA repair and cell survival. The S and G₂ phase checkpoints are predominantly regulated by checkpoint kinase 1; thus, inhibition of checkpoint kinase 1 signaling impairs DNA repair and increases tumor cell death. Normal tissues, however, have a functioning G₁ checkpoint signaling pathway that allows for DNA repair and cell survival. There is now a large body of preclinical evidence showing that checkpoint kinase inhibitors do indeed enhance the efficacy of both conventional chemotherapy and radiotherapy, and several agents have recently entered clinical trials. Excitingly, additional therapeutic opportunities for checkpoint kinase inhibitors continue to emerge as biology outside their pivotal role in cell cycle arrest is further elucidated.