TY - JOUR
T1 - Compromised CDK1 activity sensitizes BRCA-proficient cancers to PARP inhibition
AU - Johnson, Neil
AU - Li, Yu Chen
AU - Walton, Zandra E.
AU - Cheng, Katherine A.
AU - Li, Danan
AU - Rodig, Scott J.
AU - Moreau, Lisa A.
AU - Unitt, Christine
AU - Bronson, Roderick T.
AU - Thomas, Huw D.
AU - Newell, David R.
AU - D'Andrea, Alan D.
AU - Curtin, Nicola J.
AU - Wong, Kwok Kin
AU - Shapiro, Geoffrey I.
PY - 2011/7
Y1 - 2011/7
N2 - Cells that are deficient in homologous recombination, such as those that lack functional breast cancer-associated 1 (BRCA1) or BRCA2, are hypersensitive to inhibition of poly(ADP-ribose) polymerase (PARP). However, BRCA-deficient tumors represent only a small fraction of adult cancers, which might restrict the therapeutic utility of PARP inhibitor monotherapy. Cyclin-dependent kinase 1 (Cdk1) phosphorylates BRCA1, and this is essential for efficient formation of BRCA1 foci. Here we show that depletion or inhibition of Cdk1 compromises the ability of cells to repair DNA by homologous recombination. Combined inhibition of Cdk1 and PARP in BRCA-wild-type cancer cells resulted in reduced colony formation, delayed growth of human tumor xenografts and tumor regression with prolonged survival in a mouse model of lung adenocarcinoma. Inhibition of Cdk1 did not sensitize nontransformed cells or tissues to inhibition of PARP. Because reduced Cdk1 activity impaired BRCA1 function and consequently, repair by homologous recombination, inhibition of Cdk1 represents a plausible strategy for expanding the utility of PARP inhibitors to BRCA-proficient cancers.
AB - Cells that are deficient in homologous recombination, such as those that lack functional breast cancer-associated 1 (BRCA1) or BRCA2, are hypersensitive to inhibition of poly(ADP-ribose) polymerase (PARP). However, BRCA-deficient tumors represent only a small fraction of adult cancers, which might restrict the therapeutic utility of PARP inhibitor monotherapy. Cyclin-dependent kinase 1 (Cdk1) phosphorylates BRCA1, and this is essential for efficient formation of BRCA1 foci. Here we show that depletion or inhibition of Cdk1 compromises the ability of cells to repair DNA by homologous recombination. Combined inhibition of Cdk1 and PARP in BRCA-wild-type cancer cells resulted in reduced colony formation, delayed growth of human tumor xenografts and tumor regression with prolonged survival in a mouse model of lung adenocarcinoma. Inhibition of Cdk1 did not sensitize nontransformed cells or tissues to inhibition of PARP. Because reduced Cdk1 activity impaired BRCA1 function and consequently, repair by homologous recombination, inhibition of Cdk1 represents a plausible strategy for expanding the utility of PARP inhibitors to BRCA-proficient cancers.
KW - Animals
KW - BRCA1 Protein/metabolism
KW - Benzimidazoles/pharmacology
KW - Blotting, Western
KW - Breast Neoplasms/drug therapy
KW - CDC2 Protein Kinase/antagonists & inhibitors
KW - Carrier Proteins/metabolism
KW - Cell Death/drug effects
KW - Cell Line, Tumor
KW - DNA Damage/drug effects
KW - DNA-Binding Proteins
KW - Female
KW - Gene Expression Regulation, Neoplastic/drug effects
KW - Humans
KW - Indazoles/pharmacology
KW - Indoles/pharmacology
KW - Male
KW - Mice
KW - Neoplasm Transplantation
KW - Neoplasms, Experimental/metabolism
KW - Nuclear Proteins/metabolism
KW - Phosphorylation
KW - Poly(ADP-ribose) Polymerase Inhibitors
KW - RNA-Binding Proteins
UR - http://www.scopus.com/inward/record.url?scp=79960150694&partnerID=8YFLogxK
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=purepublist2023&SrcAuth=WosAPI&KeyUT=WOS:000292500800043&DestLinkType=FullRecord&DestApp=WOS
U2 - 10.1038/nm.2377
DO - 10.1038/nm.2377
M3 - Article
C2 - 21706030
SN - 1078-8956
VL - 17
SP - 875
EP - 882
JO - Nature Medicine
JF - Nature Medicine
IS - 7
ER -
