title: Inhibition of cyclin dependent kinase 9 by dinaciclib suppresses cyclin B1 expression and tumor growth in triple negative breast cancer.
abstract: Cyclin-dependent kinases (CDKs) are potential cancer therapeutic targets because of their critical role in promoting cell growth. Dinaciclib is a novel CDK inhibitor currently under clinical evaluation for the treatment of advanced malignancies. In this study, we demonstrated the anti-tumor activity of dinaciclib in triple negative breast cancer (TNBC) patient derived xenograft (PDX) and cell lines in vitro and in vivo. Treatment with dinaciclib induced cell cycle arrest at G2/M phase and marked apoptosis. These changes were accompanied by reduced phosphorylation of CDK1 and retinoblastoma (Rb) protein and decreased protein levels of cyclin B1, cMYC and survivin. We further demonstrated that siRNA knockdown of CDK9, the kinase subunit of positive transcription elongation factor b (P-TEFb), instead of CDK1 or CDK2, reduced the levels of cyclin B1 and MYC in TNBC cell lines. These data support the importance of CDK9, in addition to CDK1, in mediating the growth inhibitory effect of dinaciclib in TNBC. Further investigation of CDK9 as a therapeutic target in TNBC is needed.
authors.affiliation: Section of Medical Oncology, Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Rajput
authors.affiliation: Section of Medical Oncology, Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Nimmish
authors.initials: N
authors.lastname: Khera
authors.affiliation: Section of Medical Oncology, Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Zhanfang
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Section of Medical Oncology, Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hoog
authors.affiliation: Section of Medical Oncology, Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.|Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Shunqiang
authors.initials: S
authors.lastname: Li
authors.affiliation: Section of Medical Oncology, Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.|Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Cynthia X
authors.initials: CX
authors.lastname: Ma
mesh_terms: D000818:Animals; D017209:Apoptosis; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003497:Cyclic N-Oxides; D056744:Cyclin B1 / Q000378:metabolism*; D042863:Cyclin-Dependent Kinase 9 / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007212:Indolizines; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010766:Phosphorylation; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011726:Pyridinium Compounds / Q000494:pharmacology*; D000077022:Survivin; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: C107489:BIRC5 protein, human; D019086:Bridged Bicyclo Compounds, Heterocyclic; C534699:CCNB1 protein, human; D003497:Cyclic N-Oxides; D056744:Cyclin B1; D007212:Indolizines; D051034:Inhibitor of Apoptosis Proteins; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D011726:Pyridinium Compounds; D000077022:Survivin; C553669:dinaciclib; C467969:CDK9 protein, human; D042863:Cyclin-Dependent Kinase 9; D018844:Cyclin-Dependent Kinases
keywords: cyclin B1; cyclin dependent kinase 9; dinaciclib; patient derived xenograft; triple negative breast cancer