Poly(ADP-ribose) polymerase inhibitor CEP-8983 synergizes with bendamustine in chronic lymphocytic leukemia cells in vitro.
DNA repair aberrations and associated chromosomal instability is a feature of chronic lymphocytic leukemia (CLL). To evaluate if DNA repair insufficiencies are related to methylation changes, we examined the methylation of nine promoter regions of DNA repair proteins by bisulfide sequencing in 26 CLL primary samples and performed quantitative PCR on a subset of samples to examine BRCA1 expression. We also investigated if changes in cytogenetic or expression level of DNA repair proteins led to changes in sensitivity to a novel PARP inhibitor, CEP-8983, alone and in combination with bendamustine. No changes in promoter methylation were identified in BRCA1, BRCA2, FANC-C, FANC-F, FANC-L, ATM, MGMT, hMLH1 and H2AX except for two cases of minor BRCA1 hypermethylation. CLL samples appeared to have reduced BRCA1 mRNA expression uniformly in comparison to non-malignant lymphocytes irrespective of promoter hypermethylation. CEP-8983 displayed single agent cytotoxicity and the combination with bendamustine demonstrated synergistic cytotoxicity in the majority of CLL samples. These results were consistent across cytogenetic subgroups, including 17p deleted and previously treated patients. Our results provide rationale for further exploration of the combination of a PARP inhibitor and DNA damaging agents as a novel therapeutic strategy in CLL.
Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA.
Robert L
RL
Dilley
Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA.
Weijie
W
Poh
Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA.
Douglas E
DE
Gladstone
Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA.
James G
JG
Herman
Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA.
Margaret M
MM
Showel
Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA.
Judith E
JE
Karp
Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Michael A
MA
McDevitt
Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA. Electronic address: kpratz1@jhmi.edu.
Keith W
KW
Pratz
D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism; D000069461:Bendamustine Hydrochloride; D002227:Carbazoles / Q000494:pharmacology*; D004249:DNA Damage; D019175:DNA Methylation / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D004273:DNA, Neoplasm / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009588:Nitrogen Mustard Compounds / Q000494:pharmacology*; D010797:Phthalimides / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D017422:Sequence Analysis, DNA; D015398:Signal Transduction
D018906:Antineoplastic Agents, Alkylating; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; C523456:CEP 8983; D002227:Carbazoles; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D009588:Nitrogen Mustard Compounds; D010797:Phthalimides; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D000069461:Bendamustine Hydrochloride; D011065:Poly(ADP-ribose) Polymerases; D045643:DNA Repair Enzymes
Bendamustine; CEP-8983; Chronic lymphocytic leukemia (CLL); Poly(ADP-ribose) polymerase (PARP)