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

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 ( = 383) and the METABRIC TNBC dataset ( = 217), we found mRNA levels to be correlated with patient prognosis. High CDK7 protein expression was associated with poor prognosis within the RATHER TNBC cohort ( = 109) and the METABRIC TNBC cohort ( = 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. .

Inhibition of cyclin‐dependent kinase 7 suppresses human hepatocellular carcinoma by inducing apoptosis

“…10,18 In summary, our study showed for the first time that THZ1 may exert its anticarcinogenic effect in HCC cells both in vitro and in vivo in HCC mouse model: (a) inhibiting rapid proliferation of HCC cells; (b) promoting the apoptosis of HCC cells. Thus, THZ1 induced apoptosis by the prolonged CDK7 inhibition in HCC cells.…”

“…5,6 Kwiatkowski et al 7 reported that THZ1 can form a covalent bond by targeting a unique cysteine residue outside the cyclin-dependent kinase 7 (CDK7) kinase domain, which led to the prolonged and irreversible inactivation of CDK7. 7,[9][10][11][12][13] However, no study has been done to explore the possible effects of THZ1 on HCC yet. 8 Moreover, more and more studies illustrated that THZ1 exhibited encouraging therapeutic effects in different tumor types, such as small cell lung cancer, T-ALL, triple-negative breast cancer, ovarian cancer, and high-grade glioma.…”

A simple high-throughput approach identifies actionable drug sensitivities in patient-derived tumor organoids

“…Both THZ1 and BS-181 HCl specifically target CDK7. Nevertheless, Patient #1 PDTOs showed a strong response to the former but no response to the latter which could be attributed to the different activity of the two as recently observed in breast cancer 28 .…”

The essential and multifunctional TFIIH complex

“…Numerous cancers appear to be dependent on elevated CDK7 activity to drive their oncogenic state . Because of its role in cell cycle regulation, CDK7 activity cannot be entirely de‐coupled from its broad transcriptional effects.…”

“…Numerous cancers appear to be dependent on elevated CDK7 activity to drive their oncogenic state. 192,193 Because of its role in cell cycle regulation, CDK7 activity cannot be entirely de-coupled from its broad transcriptional effects. However, elevated expression of oncogenes is enabled by clusters of enhancers, or super-enhancers, [194][195][196] that require CDK7 activity to maintain their high-level expression.…”