Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.815945
Title: Exploring the potential of CDK7 inhibition to permanently arrest cancer cells
Author: Wilson, Gemma Alice
ISNI:       0000 0004 9359 1216
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2020
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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.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.815945  DOI: Not available
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