Investigating the mechanisms of action of cyclin-dependent kinase 7 (CDK7) inhibitors in breast cancer
File(s)
Author(s)
Jurgaityte, Kaste
Type
Thesis or dissertation
Abstract
Breast cancer is the most common cancer worldwide, with tumour development and progression driven by the estrogen receptor (ER) in most cases. ER inhibitors are now standard-of-care therapies for ER+ breast cancer and have been successful in reducing mortality since their introduction five decades ago. However, many patients relapse with advanced disease necessitating the development of alternative therapies. Previously, our lab identified cyclin-dependent kinase 7 (CDK7) as a potential cancer therapeutic target. CDK7 controls expression of protein coding genes by phosphorylating RNA polymerase II (Pol-II). CDK7 is also required for phosphorylation of CDKs that control appropriate cell cycle progression. Because transcriptional and cell cycle processes are both commonly dysregulated in cancer, our lab has developed selective small molecule inhibitors of CDK7, demonstrating potent tumour growth inhibition. Samuraciclib has emerged from this as an orally bioavailable CDK7 inhibitor that has demonstrated encouraging levels of efficacy in ER+ breast cancer patients in a Phase I clinical trial. A fundamental understanding of the mechanisms of sensitivity and resistance to samuraciclib is essential for guiding appropriate and informed treatment regimens. In this work, I explore mechanisms of samuraciclib-induced cell growth arrest and cell death using a combination of CRISPR-Cas9 genomic and quantitative proteomics screens. I show that samuraciclib-induced cell growth arrest is highly dependent on a functional PI3K/Akt/mTOR pathway such that PIK3CA-activating mutations amplify growth arrest. To profile the molecular response to samuraciclib, I performed a high-throughput, quantitative mass spectrometry analysis of ER+ breast cancer cells treated with samuraciclib. In addition to confirming alterations in proteins in PI3K/Akt/mTOR, global proteomics identified altered levels of proteins implicated in ferroptosis, a recently discovered non-apoptotic cell death pathway. I demonstrate that samuraciclib sensitizes breast cancer cells to ferroptosis-directed cell death and highlight new combination therapies that could enhance the clinical utility of CDK7 inhibitors in cancer patients.
Version
Open Access
Date Issued
2024-03-01
Date Awarded
2024-08-01
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Ali, Simak
Buluwela, Laki
Sava, Georgina
Sponsor
One More City
Publisher Department
Department of Surgery & Cancer
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)