title: Targeting DNA Replication Stress for Cancer Therapy.
abstract: The human cellular genome is under constant stress from extrinsic and intrinsic factors, which can lead to DNA damage and defective replication. In normal cells, DNA damage response (DDR) mediated by various checkpoints will either activate the DNA repair system or induce cellular apoptosis/senescence, therefore maintaining overall genomic integrity. Cancer cells, however, due to constitutive growth signaling and defective DDR, may exhibit "replication stress" -a phenomenon unique to cancer cells that is described as the perturbation of error-free DNA replication and slow-down of DNA synthesis. Although replication stress has been proven to induce genomic instability and tumorigenesis, recent studies have counterintuitively shown that enhancing replicative stress through further loosening of the remaining checkpoints in cancer cells to induce their catastrophic failure of proliferation may provide an alternative therapeutic approach. In this review, we discuss the rationale to enhance replicative stress in cancer cells, past approaches using traditional radiation and chemotherapy, and emerging approaches targeting the signaling cascades induced by DNA damage. We also summarize current clinical trials exploring these strategies and propose future research directions including the use of combination therapies, and the identification of potential new targets and biomarkers to track and predict treatment responses to targeting DNA replication stress.
authors.affiliation: Division of Hematology, Oncology and Blood & Marrow Transplantation, Department of Internal Medicine, Holden Comprehensive Cancer Center, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA. jun-zhang-1@uiowa.edu.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Division of Hematology, Oncology and Blood & Marrow Transplantation, Department of Internal Medicine, Holden Comprehensive Cancer Center, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA. qun-dai@uiowa.edu.
authors.forename: Qun
authors.initials: Q
authors.lastname: Dai
authors.affiliation: Division of Cancer Biology, Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, 1365C Clifton Road NE, Atlanta, GA 30322, USA. dpark33@emory.edu.
authors.forename: Dongkyoo
authors.initials: D
authors.lastname: Park
authors.affiliation: Division of Cancer Biology, Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, 1365C Clifton Road NE, Atlanta, GA 30322, USA. xdeng4@emory.edu.
authors.forename: Xingming
authors.initials: X
authors.lastname: Deng
keywords: DNA replication stress; cancer; targeted therapy