Targeting DNA replication stress for cancer therapy

• Type of Material: Article
• Authors: Jun Zhang, University of Iowa; Qun Dai, University of Iowa; Dongkyoo Park, Emory University; Xingming Deng, Emory University
• Language: English
• Date: 2016-08-19
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2016 by the authors; licensee MDPI, Basel, Switzerland.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/genes7080051
• Title of Journal or Parent Work: Genes
• ISSN: 2073-4425
• Volume: 7
• Issue: 8
• Start Page: 51
• End Page: 51
• Grant/Funding Information: This work is supported by the University of Iowa Faculty Start-up Funds (JZ) and National Institutes of Health Grants 2R01CA136534-06 and R01CA193828 (XD).
• Keywords: targeted therapy; DNA replication stress; cancer
• Research Categories: Health Sciences, Oncology; Biology, Genetics

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.