Inhibition of cyclin dependent kinase 9 by dinaciclib suppresses cyclin B1 expression and tumor growth in triple negative breast cancer

Sandeep Rajput; Nimmish Khera; Zhanfang Guo; Jeremy Hoog; Shunqiang Li; Cynthia X. Ma

doi:10.18632/oncotarget.10870

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Research Papers:

Inhibition of cyclin dependent kinase 9 by dinaciclib suppresses cyclin B1 expression and tumor growth in triple negative breast cancer

Sandeep Rajput, Nimmish Khera, Zhanfang Guo, Jeremy Hoog, Shunqiang Li and Cynthia X. Ma _

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Oncotarget. 2016; 7:56864-56875. https://doi.org/10.18632/oncotarget.10870

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Abstract

Sandeep Rajput1, Nimmish Khera1, Zhanfang Guo1, Jeremy Hoog1, Shunqiang Li1,2, Cynthia X. Ma1,2

1Section of Medical Oncology, Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA

2Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA

Correspondence to:

Cynthia X. Ma, email: [email protected]

Keywords: dinaciclib, triple negative breast cancer, patient derived xenograft, cyclin B1, cyclin dependent kinase 9

Received: April 08, 2016 Accepted: July 10, 2016 Published: July 28, 2016

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.

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Research Papers:

Inhibition of cyclin dependent kinase 9 by dinaciclib suppresses cyclin B1 expression and tumor growth in triple negative breast cancer

Abstract