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Ref Type Journal Article
PMID (26719576)
Authors Alagpulinsa DA, Ayyadevara S, Yaccoby S, Shmookler Reis RJ
Title A Cyclin-Dependent Kinase Inhibitor, Dinaciclib, Impairs Homologous Recombination and Sensitizes Multiple Myeloma Cells to PARP Inhibition.
Journal Molecular cancer therapeutics
Vol 15
Issue 2
Date 2016 Feb
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown multiple myeloma not applicable Dinaciclib + Doxorubicin Preclinical - Cell culture Actionable In a preclinical study, the combination of Dinaciclib (SCH 727965) and Adriamycin (doxorubicin) demonstrated synergy in multiple myeloma cell lines in culture, resulting in decreased cell viability (PMID: 26719576). 26719576
Unknown unknown multiple myeloma not applicable Dinaciclib Preclinical - Cell line xenograft Actionable In a preclinical study, Dinaciclib (SCH 727965) decreased cell viability and growth of multiple myeloma cell lines in culture, and decreased tumor growth in multiple myeloma cell line xenograft models (PMID: 26719576). 26719576
Unknown unknown multiple myeloma not applicable B02 + Veliparib Preclinical - Cell culture Actionable In a preclinical study, the addition of B02 resulted in increased sensitivity to Veliparib (ABT-888), in a multiple myeloma cell line in culture, leading decreased cell viability (PMID: 26719576). 26719576
Unknown unknown multiple myeloma not applicable Dinaciclib + Veliparib Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of Veliparib (ABT-888) and Dinaciclib (SCH 727965) had a synergistic effect on decreasing survival of multiple myeloma cell lines in culture, and resulted in delayed tumor growth and improved survival of multiple myeloma cell line xenograft models compared to either agent alone (PMID: 26719576). 26719576