Understanding the mechanism of action of transcriptional inhibitors in breast cancer
File(s)
Author(s)
Nguyen, Thuy Mai Van
Type
Thesis
Abstract
Cancer cells frequently feature aberrant transcriptional program that sustain their oncogenic features including growth and progression. In this study, I systematically characterized the super-enhancer landscapes of breast cancer cells and revealed many super-enhancer-associated genes underlying the oncogenic mechanisms of breast cancers. Enhancer profiling also allowed the identification of core transcriptional regulatory circuitries that are maintained by cell line-specific and common transcription factors. These findings identify cancer drivers, such as TOMM20, ABHD11-AS1, some of which have not previously been linked to breast cancer. In addition to transcriptional dysregulation, control of cell cycle progression is often deregulated in cancer. Both transcription and cell cycle control are regulated by cyclin-dependent kinase-7 (CDK7), highlighting the potential of CDK7 inhibitors for cancer treatment. Our laboratory has developed selective CDK7 inhibitors, one of which, ICEC0942, has been progressed to clinical trials. Utilizing genomic and transcriptional studies, I show that ICEC0942 inhibits global Pol II recruitment to gene promoters and gene bodies and consequently the expression of Pol II-directed genes. RNA-sequencing in breast cancer cell lines identified pathways and genes that are especially sensitive to CDK7 inhibition by ICEC0942. Confirmation of the profiling results, together with use of drugs targeting the identified genes, show that CDK7 inhibition by ICEC0942 stimulates p53, resulting in increased expression of p53-responsive genes. I also demonstrated that ICEC0942 synergises with the p53 activator Nutlin-3A, in inhibiting cancer cell growth. Other genes whose expression is particularly sensitive to ICEC0942, highlighted the P-TEFb transcriptional complex. I show that inhibitors of the P-TEFb complex synergise potently with CDK7 inhibitors. Taken together, new insights into the mechanisms by which CDK7 inhibitors, particularly ICEC0942, work to inhibit the growth of cancer cells has identified potential biomarkers and combination drugs. Translation to the clinical setting could aid patient stratification and improve the utility of CDK7 inhibitors in treatment of cancer patients.
Version
Open Access
Date Issued
2020-02
Date Awarded
2020-08
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Ali, Simak
Buluwela, Lakjaya
Sponsor
Cancer Research UK
Publisher Department
Department of Surgery & Cancer
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)