Journal
FEBS JOURNAL
Volume 283, Issue 2, Pages 232-245Publisher
WILEY
DOI: 10.1111/febs.13574
Keywords
anti-cancer therapy; DNA damage; DNA metabolism; oncogenic stress; replication stress
Categories
Funding
- European Union - Marie Curie-FP7-People programme [332428]
- Torsten and Ragnar Soderberg Foundation
- Knut and Alice Wallenberg Foundation
- Swedish Research Council
- European Research Council
- Swedish Cancer Society
- Swedish Children's Cancer Foundation
- AFA insurance
- Swedish Pain Relief Foundation
- Goran Gustafsson Foundation
- Vinnova
- Swedish Foundation for Strategic Research
Ask authors/readers for more resources
Anti-cancer therapies targeting and damaging the DNA have been extensively used in the last 50 years since the discovery of nitrogen mustards, antimetabolites and platin agents. The use of these drugs is often limited by dose-limiting side effects related to their poor specificity. In recent years, much effort has been put on the discovery and development of compounds that would exploit defects in DNA repair in cancer cells such as Wee1, Chk1 or PARP1 inhibitors. However, not all cancers respond to these inhibitors. Recently, new developments towards specifically targeting broader characteristics of cancer such as replication stress (RS) and lost redox homeostasis have emerged. Oncogenes induce proliferation signals, which also result in replication-associated DNA damage, i.e. RS. Our knowledge into overall causes of RS, lesions produced and how these are signalled in cells to activate cell cycle checkpoints is evolving. Inhibition of ATR, which would normally keep non-deleterious levels of RS, induces intolerable RS levels for cancer cells. Interestingly, links between replication and transcription appear to underlie RS along with a reduction of the dNTP pool. Remarkably, sanitization of the dNTP pool by MutT homologue 1, impeding incorporation of oxidized dNTPs into the DNA, seems to be crucial for cancer cell survival. In this minireview we present an overview of current and novel strategies to target DNA repair and exploit DNA damage to treat cancer. We present the current models for cancer-associated RS as well as cancer phenotypic lethality. Both strategies are poised to better target cancer cells and reduce side effects.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available