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Therapeutic rationale to target highly expressed CDK7 conferring poor outcomes in triple-negative breast cancer

Li, Bo; Chonghaile, Triona Ni; Fan, Yue; Madden, Stephen F.; Klinger, Rut; O'Connor, Aisling E.; Walsh, Louise; O'Hurley, Gillian; Udupi, Girish Mallya and Joseph, Jesuchristopher, et al. (2017) In Cancer Research 77(14). p.3834-3845
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 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... (More)

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.

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Cancer Research
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77
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14
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12 pages
publisher
American Association for Cancer Research Inc.
external identifiers
  • scopus:85024102927
  • wos:000405677500012
ISSN
0008-5472
DOI
10.1158/0008-5472.CAN-16-2546
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English
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yes
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a7046783-b828-4010-a831-16b0d4b4cf12
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2017-08-02 10:51:22
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2017-09-18 11:40:49
@article{a7046783-b828-4010-a831-16b0d4b4cf12,
  abstract     = {<p>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.</p>},
  author       = {Li, Bo and Chonghaile, Triona Ni and Fan, Yue and Madden, Stephen F. and Klinger, Rut and O'Connor, Aisling E. and Walsh, Louise and O'Hurley, Gillian and Udupi, Girish Mallya and Joseph, Jesuchristopher and Tarrant, Finbarr and Conroy, Emer and Gaber, Alexander and Chin, Suet-Feung and Bardwell, Helen A and Provenzano, Elena and Crown, John P. and Dubois, Thierry and Linn, Sabine and Jirstrom, Karin and Caldas, Carlos and O'Connor, Darran P. and Gallagher, William M},
  issn         = {0008-5472},
  language     = {eng},
  month        = {07},
  number       = {14},
  pages        = {3834--3845},
  publisher    = {American Association for Cancer Research Inc.},
  series       = {Cancer Research},
  title        = {Therapeutic rationale to target highly expressed CDK7 conferring poor outcomes in triple-negative breast cancer},
  url          = {http://dx.doi.org/10.1158/0008-5472.CAN-16-2546},
  volume       = {77},
  year         = {2017},
}