Compromised CDK1 activity sensitizes BRCA-proficient cancers to PARP inhibition.

Abstract

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.

• Authors: Neil Johnson, Yu-Chen Li, Zandra E Walton, Katherine A Cheng, Danan Li, Scott J Rodig, Lisa A Moreau, Christine Unitt, Roderick T Bronson, Huw D Thomas, David R Newell, Alan D D'Andrea, Nicola J Curtin, Kwok-Kin Wong, Geoffrey I Shapiro
• Journal: Nature medicine (Nat Med) Vol. 17 Issue 7 Pg. 875-82 (Jun 26 2011) ISSN: 1546-170X [Electronic] United States
• PMID: 21706030 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• BRCA1 Protein
• Benzimidazoles
• Carrier Proteins
• DNA-Binding Proteins
• Indazoles
• Indoles
• N-((5-(3-(4,6-difluoro-1H-benzimidazol-2-yl)-1H-indazol-5-yl)-4-methylpyridin-3-yl)methyl)ethanamine
• Nuclear Proteins
• Poly(ADP-ribose) Polymerase Inhibitors
• RNA-Binding Proteins
• Rad51ap1 protein, mouse
• rucaparib
• CDC2 Protein Kinase

Topics

• Animals
• BRCA1 Protein (metabolism, physiology)
• Benzimidazoles (pharmacology)
• Blotting, Western
• Breast Neoplasms (drug therapy, metabolism, physiopathology)
• CDC2 Protein Kinase (antagonists & inhibitors, metabolism, physiology)
• Carrier Proteins (metabolism, physiology)
• Cell Death (drug effects)
• Cell Line, Tumor
• DNA Damage (drug effects, physiology)
• DNA-Binding Proteins
• Female
• Gene Expression Regulation, Neoplastic (drug effects, physiology)
• Humans
• Indazoles (pharmacology)
• Indoles (pharmacology)
• Male
• Mice
• Neoplasm Transplantation
• Neoplasms, Experimental (metabolism, physiopathology)
• Nuclear Proteins (metabolism, physiology)
• Phosphorylation
• Poly(ADP-ribose) Polymerase Inhibitors
• RNA-Binding Proteins