Type

Journal Article

Authors

William M Gallagher
Darran P O'Connor
Carlos Caldas
Karin Jirstrom
Sabine Linn
Thierry Dubois
John Crown
Elena Provenzano
Helen A Bardwell
Suet-Feung Chin
and 13 others

Subjects

Biochemistry

Topics
cell cycle protein expression human cells outcomes rna polymerase ii therapeutic triple negative breast cancer bcl 2

Therapeutic Rationale to Target Highly Expressed CDK7 Conferring Poor Outcomes in Triple-Negative Breast Cancer. (2016)

Abstract Triple-negative breast cancer (TNBC) patients commonly exhibit poor prognosis and high relapse after treatment, but there remains a lack of biomarkers and effective targeted therapies for this disease. Here, we report evidence highlighting the cell-cycle-related kinase CDK7 as a driver and candidate therapeutic target in TNBC. Using publicly available transcriptomic data from a collated set of TNBC patients (n = 383) and the METABRIC TNBC dataset (n = 217), we found CDK7 mRNA levels to be correlated with patient prognosis. High CDK7 protein expression was associated with poor prognosis within the RATHER TNBC cohort (n = 109) and the METABRIC TNBC cohort (n = 203). The highly specific CDK7 kinase inhibitors, BS-181 and THZ1, each downregulated CDK7-mediated phosphorylation of RNA polymerase II, indicative of transcriptional inhibition, with THZ1 exhibiting 500-fold greater potency than BS-181. Mechanistic investigations revealed that the survival of MDA-MB-231 TNBC cells relied heavily on the BCL-2/BCL-XL signaling axes in cells. Accordingly, we found that combining the BCL-2/BCL-XL inhibitors ABT-263/ABT199 with the CDK7 inhibitor THZ1 synergized in producing growth inhibition and apoptosis of human TNBC cells. Collectively, our results highlight elevated CDK7 expression as a candidate biomarker of poor prognosis in TNBC, and they offer a preclinical proof of concept for combining CDK7 and BCL-2/BCL-XL inhibitors as a mechanism-based therapeutic strategy to improve TNBC treatment. Cancer Res; 77(14); 3834-45. ©2017 AACR.
Collections Ireland -> Royal College of Surgeons in Ireland -> PubMed

Full list of authors on original publication

William M Gallagher, Darran P O'Connor, Carlos Caldas, Karin Jirstrom, Sabine Linn, Thierry Dubois, John Crown, Elena Provenzano, Helen A Bardwell, Suet-Feung Chin and 13 others

Experts in our system

1
William M Gallagher
University College Dublin
Total Publications: 148
 
2
Darran P O'Connor
Royal College of Surgeons in Ireland
Total Publications: 43
 
3
Karin Jirstrom
University College Dublin
 
4
John Crown
Dublin City University
Total Publications: 104