Biomarker-Guided Development of DNA Repair Inhibitors

Anti-cancer drugs targeting the DNA damage response (DDR) exploit genetic or functional defects in this pathway through synthetic lethal mechanisms. For example, defects in homologous recombination (HR) repair arise in cancer cells through inherited or acquired mutations in BRCA1, BRCA2, or other ge...

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Published in:Molecular cell Vol. 78; no. 6; p. 1070
Main Authors: Cleary, James M, Aguirre, Andrew J, Shapiro, Geoffrey I, D'Andrea, Alan D
Format: Journal Article
Language:English
Published: United States 18.06.2020
Subjects:
Animals
Antineoplastic Agents - therapeutic use
Biomarkers, Pharmacological
DNA Damage - drug effects
DNA End-Joining Repair - drug effects
DNA Repair - drug effects
DNA Repair - genetics
DNA Repair - physiology
Genes, BRCA1 - drug effects
Homologous Recombination
Humans
Neoplasms - drug therapy
Poly(ADP-ribose) Polymerase Inhibitors - pharmacology
Poly(ADP-ribose) Polymerases - metabolism
cell-cycle kinases
DNA repair
polymerase theta
PARP inhibitor
ISSN:1097-4164, 1097-4164
Online Access:Get more information
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Summary:Anti-cancer drugs targeting the DNA damage response (DDR) exploit genetic or functional defects in this pathway through synthetic lethal mechanisms. For example, defects in homologous recombination (HR) repair arise in cancer cells through inherited or acquired mutations in BRCA1, BRCA2, or other genes in the Fanconi anemia/BRCA pathway, and these tumors have been shown to be particularly sensitive to inhibitors of the base excision repair (BER) protein poly (ADP-ribose) polymerase (PARP). Recent work has identified additional genomic and functional assays of DNA repair that provide new predictive and pharmacodynamic biomarkers for these targeted therapies. Here, we examine the development of selective agents targeting DNA repair, including PARP inhibitors; inhibitors of the DNA damage kinases ataxia-telangiectasia and Rad3 related (ATR), CHK1, WEE1, and ataxia-telangiectasia mutated (ATM); and inhibitors of classical non-homologous end joining (cNHEJ) and alternative end joining (Alt EJ). We also review the biomarkers that guide the use of these agents and current clinical trials with these therapies.
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ISSN:1097-4164
1097-4164
DOI:10.1016/j.molcel.2020.04.035