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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Vydané v:	Molecular cell Ročník 78; číslo 6; s. 1070
Hlavní autori:	Cleary, James M, Aguirre, Andrew J, Shapiro, Geoffrey I, D'Andrea, Alan D
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States 18.06.2020
Predmet:	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
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Abstract	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.
AbstractList	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. 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.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.
Author	D'Andrea, Alan D Cleary, James M Shapiro, Geoffrey I Aguirre, Andrew J
Author_xml	– sequence: 1 givenname: James M surname: Cleary fullname: Cleary, James M organization: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA – sequence: 2 givenname: Andrew J surname: Aguirre fullname: Aguirre, Andrew J organization: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA – sequence: 3 givenname: Geoffrey I surname: Shapiro fullname: Shapiro, Geoffrey I organization: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, MA 02215, USA – sequence: 4 givenname: Alan D surname: D'Andrea fullname: D'Andrea, Alan D email: alan_dandrea@dfci.harvard.edu organization: Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: alan_dandrea@dfci.harvard.edu
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SubjectTerms	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
Title	Biomarker-Guided Development of DNA Repair Inhibitors
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