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

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

doi:10.18632/oncotarget.10870

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.

Highlights

Triple negative breast cancer (TNBC) refers to the subgroup of breast cancers that are negative for estrogen receptor (ER), progesterone receptor (PR), and HER2
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 triple negative breast cancer (TNBC) cell lines
We first performed 2D clonogenic assay to determine the effect of dinaciclib on in vitro cell growth of 3 patient derived xenograft (PDX) models as described in materials and methods [WHIM3 (WT TP53), WHIM12 and WHIM21], 3 TNBC cell lines [BT549, MDA-MB-231, and HCC1806, and 3 ER+ cell lines [BT474 (WT TP53), MCF7 (WT TP53) and T47D]

Summary

Introduction

Triple negative breast cancer (TNBC) refers to the subgroup of breast cancers that are negative for estrogen receptor (ER), progesterone receptor (PR), and HER2. It accounts for about 15% of invasive breast cancer diagnosis and is often associated with high tumor grade, aggressive clinical course, and adverse prognosis [1]. Compared to the availability of targeted agents for ER+ or HER2+ breast cancer, treatment for TNBC is limited to cytotoxic chemotherapy which is often ineffective, leading to recurrence and death [1, 2]. Targeting cell cycle regulatory proteins presents an attractive therapeutic strategy in TNBC [6,7,8]

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