title: A Cyclin-Dependent Kinase Inhibitor, Dinaciclib, Impairs Homologous Recombination and Sensitizes Multiple Myeloma Cells to PARP Inhibition.
abstract: PARP1/2 are required for single-strand break repair, and their inhibition causes DNA replication fork collapse and double-strand break (DSB) formation. These DSBs are primarily repaired via homologous recombination (HR), a high-fidelity repair pathway. Should HR be deficient, DSBs may be repaired via error-prone nonhomologous end-joining mechanisms, or may persist, ultimately resulting in cell death. The combined disruption of PARP and HR activities thus produces synthetic lethality. Multiple myeloma cells are characterized by chromosomal instability and pervasive DNA damage, implicating aberrant DNA repair. Cyclin-dependent kinases (CDK), upstream modulators of HR, are dysregulated in multiple myeloma. Here, we show that a CDK inhibitor, dinaciclib, impairs HR repair and sensitizes multiple myeloma cells to the PARP1/2 inhibitor ABT-888. Dinaciclib abolishes ABT-888-induced BRCA1 and RAD51 foci and potentiates DNA damage, indicated by increased γH2AX foci. Dinaciclib treatment reduces expression of HR repair genes, including Rad51, and blocks BRCA1 phosphorylation, a modification required for HR repair, thus inhibiting HR repair of chromosome DSBs. Cotreatment with dinaciclib and ABT-888 in vitro resulted in synthetic lethality of multiple myeloma cells, but not normal CD19(+) B cells, and slowed growth of multiple myeloma xenografts in SCID mice almost two-fold. These findings support combining dinaciclib with PARP inhibitors for multiple myeloma therapy. Mol Cancer Ther; 15(2); 241-50. ©2015 AACR.
authors.affiliation: McClellan Veterans Medical Center, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas. Department of Geriatrics, University of Arkansas for Medical Science, Little Rock, Arkansas.
authors.forename: David A
authors.initials: DA
authors.lastname: Alagpulinsa
authors.affiliation: McClellan Veterans Medical Center, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas. Department of Geriatrics, University of Arkansas for Medical Science, Little Rock, Arkansas.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Ayyadevara
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Shmuel
authors.initials: S
authors.lastname: Yaccoby
authors.affiliation: McClellan Veterans Medical Center, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas. Department of Geriatrics, University of Arkansas for Medical Science, Little Rock, Arkansas. rjsr@uams.edu.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Shmookler Reis
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003497:Cyclic N-Oxides; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D059765:Homologous Recombination / Q000187:drug effects*; D006801:Humans; D007212:Indolizines; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000008:administration & dosage* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D001562:Benzimidazoles; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003497:Cyclic N-Oxides; D007212:Indolizines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011726:Pyridinium Compounds; C521013:veliparib; C553669:dinaciclib; D018844:Cyclin-Dependent Kinases