Epigenetic deregulation of DNA repair and its potential for therapy.
Epigenetic silencing of essential components of DNA repair pathways is a common event in many tumor types, and comprise O6-methylguanine-DNA methyltransferase (MGMT), human mut L homolog 1 (hMLH1), Werner syndrome gene (WRN), breast cancer susceptibility gene 1 (BRCA1), and genes of the Fanconi anemia pathway. Most interestingly, some of these alterations become the Achilles heel of the affected tumors upon treatment with certain classes of anticancer agents. That is, patients whose tumors carry such defects can be stratified for respective therapy rendering some classic DNA damaging agents, such as alkylators or DNA crosslinking agents, into "targeted therapies." Here we review some of the affected repair pathways that, when inactivated, sensitize the tumors to specific drugs and are thus exploitable for individualized therapy.
Hegi
Monika E
ME
Laboratory of Brain Tumor Biology and Genetics, University Hospital Lausanne (CHUV) and University of Lausanne, Lausanne, Switzerland. Monika.Hegi@chuv.ch
Sciuscio
Davide
D
Murat
Anastasia
A
Levivier
Marc
M
Stupp
Roger
R
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000627:therapeutic use*; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics*; D016503:Drug Delivery Systems / Q000379:methods; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
D000970:Antineoplastic Agents