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Exploring the potential of CDK7 inhibition to permanently arrest cancer cells

Wilson, Gemma Alice; (2020) Exploring the potential of CDK7 inhibition to permanently arrest cancer cells. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Despite the clinical success of some targeted therapies in treating cancer, the response to them is often temporary, due to treatment resistance developing. Therefore, researchers must continue to look for novel ways to treat cancer. A number of groups are developing CDK7 inhibitors as anti-cancer drugs. CDK7 is a protein that has two major roles in cells - regulation of RNA polymerase II-mediated transcription and cell cycle progression as the CDK activating kinase. Both of these cellular processes are often deregulated during oncogenesis. Our collaborators at Imperial College London have developed a novel CDK7 inhibitor, ICEC0942, that is currently in Phase I/II clinical trials. ICEC0942 has been shown to inhibit the proliferation of cancer cell lines, but the mechanism by which it does this has not been previously determined. The work presented in this thesis aimed to understand this better. To establish its mechanism of action, we studied the effects of ICEC0942 on non- transformed RPE1 cells. Our data shows that ICEC0942 induces a permanent cell cycle arrest, with the cells displaying phenotypic characteristics of senescence. This contrasts to a more well-studied CDK7 inhibitor THZ1, which inhibits cell proliferation by inducing apoptosis. The data from a chemogenetic screen with ICEC0942, carried out by collaborators at the University of Montreal, revealed that activation of mTOR signalling was positively correlated with ICEC0942 efficacy. Further experiments confirmed these results by showing that inhibition of the mTOR signalling pathway partially rescued characteristics of senescence induced by ICEC0942 treatment. This was demonstrated in RPE1 cells and MCF7 cells, a breast cancer cell line. From this we hypothesise that ICEC0942 induces senescence by uncoupling cell division and cell growth, and that mTOR signalling plays an important role in this. Our future work will focus on how to use this insight to guide the clinical use of ICEC0942.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Exploring the potential of CDK7 inhibition to permanently arrest cancer cells
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2020. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Lab for Molecular Cell Bio MRC-UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10097589
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