TY - JOUR
T1 - Therapeutic rationale to target highly expressed CDK7 conferring poor outcomes in triple-negative breast cancer
AU - Li, Bo
AU - Chonghaile, Triona Ni
AU - Fan, Yue
AU - Madden, Stephen F.
AU - Klinger, Rut
AU - O'Connor, Aisling E.
AU - Walsh, Louise
AU - O'Hurley, Gillian
AU - Udupi, Girish Mallya
AU - Joseph, Jesuchristopher
AU - Tarrant, Finbarr
AU - Conroy, Emer
AU - Gaber, Alexander
AU - Chin, Suet-Feung
AU - Bardwell, Helen A
AU - Provenzano, Elena
AU - Crown, John
AU - Dubois, Thierry
AU - Linn, Sabine
AU - Jirstrom, Karin
AU - Caldas, Carlos
AU - O'Connor, Darran P
AU - Gallagher, William M
N1 - Funding Information:
We thank all members of the RATHER consortium, in particular Prof. Rene Bernards from the Netherlands Cancer Institute (Amsterdam, the Netherlands), who provided constructive suggestions for this study. We also thank Dr. Nathanael Gray from the Dana-Farber Cancer Institute (Boston, MA) for the kind gift of the THZ1 inhibitor. This studywas supported by RATHER (Rational Therapy for Breast Cancer), a Collaborative Project funded under the European Union 7th Framework Programme (grant agreement no. 258967), the Irish Cancer Society Collaborative Cancer Research Centre BREAST-PREDICT (CCRC13GAL), and the Science Foundation Ireland Investigator Programme OPTi-PREDICT (grant code 15/IA/3104).
Publisher Copyright:
2017 American Association for Cancer Research.
PY - 2017/7/15
Y1 - 2017/7/15
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85024102927
U2 - 10.1158/0008-5472.CAN-16-2546
DO - 10.1158/0008-5472.CAN-16-2546
M3 - Article
C2 - 28455421
AN - SCOPUS:85024102927
SN - 0008-5472
VL - 77
SP - 3834
EP - 3845
JO - Cancer Research
JF - Cancer Research
IS - 14
ER -