Search: onr:"swepub:oai:lup.lub.lu.se:a7046783-b828-4010-a831-16b0d4b4cf12" >
Therapeutic rationa...
Therapeutic rationale to target highly expressed CDK7 conferring poor outcomes in triple-negative breast cancer
-
- Li, Bo (author)
- University College Dublin
-
- Chonghaile, Triona Ni (author)
- Royal College of Surgeons in Ireland
-
- Fan, Yue (author)
- University College Dublin
-
show more...
-
- Madden, Stephen F. (author)
- Royal College of Surgeons in Ireland
-
- Klinger, Rut (author)
- University College Dublin
-
- O'Connor, Aisling E. (author)
- University College Dublin
-
- Walsh, Louise (author)
- Royal College of Surgeons in Ireland
-
- O'Hurley, Gillian (author)
- OncoMark Ltd
-
- Udupi, Girish Mallya (author)
- OncoMark Ltd
-
- Joseph, Jesuchristopher (author)
- OncoMark Ltd
-
- Tarrant, Finbarr (author)
- University College Dublin
-
- Conroy, Emer (author)
- University College Dublin
-
- Gaber, Alexander (author)
- Lund University,Lunds universitet,Tumörmikromiljö,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Tumor microenvironment,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine
-
- Chin, Suet-Feung (author)
- University of Cambridge
-
- Bardwell, Helen A (author)
- University of Cambridge
-
- Provenzano, Elena (author)
- University of Cambridge
-
- Crown, John P. (author)
- St Vincent's University Hospital
-
- Dubois, Thierry (author)
- Curie Institute, Paris
-
- Linn, Sabine (author)
- Netherlands Cancer Institute
-
- Jirstrom, Karin (author)
- Lund University,Lunds universitet,Tumörmikromiljö,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Tumor microenvironment,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine
-
- Caldas, Carlos (author)
- University of Cambridge
-
- O'Connor, Darran P. (author)
- Royal College of Surgeons in Ireland
-
- Gallagher, William M (author)
- University College Dublin,OncoMark Ltd
-
show less...
-
(creator_code:org_t)
- 2017
- 2017
- English 12 s.
-
In: Cancer Research. - 0008-5472. ; 77:14, s. 3834-3845
- Related links:
-
http://dx.doi.org/10...
-
show more...
-
https://lup.lub.lu.s...
-
https://doi.org/10.1...
-
show less...
Abstract
Subject headings
Close
- 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 ¼ 383) and the METABRIC TNBC dataset (n ¼ 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 ¼ 109) and the METABRIC TNBC cohort (n ¼ 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Publication and Content Type
- art (subject category)
- ref (subject category)
Find in a library
To the university's database
- By the author/editor
-
Li, Bo
-
Chonghaile, Trio ...
-
Fan, Yue
-
Madden, Stephen ...
-
Klinger, Rut
-
O'Connor, Aislin ...
-
show more...
-
Walsh, Louise
-
O'Hurley, Gillia ...
-
Udupi, Girish Ma ...
-
Joseph, Jesuchri ...
-
Tarrant, Finbarr
-
Conroy, Emer
-
Gaber, Alexander
-
Chin, Suet-Feung
-
Bardwell, Helen ...
-
Provenzano, Elen ...
-
Crown, John P.
-
Dubois, Thierry
-
Linn, Sabine
-
Jirstrom, Karin
-
Caldas, Carlos
-
O'Connor, Darran ...
-
Gallagher, Willi ...
-
show less...
- About the subject
-
- MEDICAL AND HEALTH SCIENCES
-
MEDICAL AND HEAL ...
-
and Clinical Medicin ...
-
and Cancer and Oncol ...
- Articles in the publication
-
Cancer Research
- By the university
-
Lund University