Validating Greatwall kinase as a potential target in cancer therapy

Eckert, Aimee (2019) Validating Greatwall kinase as a potential target in cancer therapy. Doctoral thesis (PhD), University of Sussex.

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Abstract

All cancers have deregulated cell proliferation. Therefore, full understanding of cell cycle control is needed to identify protein targets that can lead to the development of novel therapies, as well as improving our knowledge and use of existing ones. Greatwall kinase (GWL), a protein essential for mitotic entry in human cells, is gaining interest in cancer research as it has been shown to be upregulated in various cancers. My research aims to decipher the mechanisms of Triple Negative breast cancer (TNBC) cell sensitivity to GWL knockdown, as this information could provide scope for the development of novel drugs to be synergised with existing treatments. We have shown that depletion of GWL via shRNA in certain TNBC cell lines causes harmful cell proliferation defects. Surprisingly these effects coincided with significant depletion of replicating cells, rather than pronounced mitotic defects. This suggests that certain cancer cells are especially reliant on GWL and that GWL may have other functions apart from its known role in suppressing mitotic PP2A activity. To further investigate these novel functions, we have performed a siRNA cell viability screen comparing cells lacking and expressing GWL. This led to the identification of a novel synthetic lethality between CDK4 (a kinase whose activity is restricted to G1-S phase) and GWL (canonically active in mitosis). Further analysis revealed that this synergy of GWL and CDK4 does not involve the known downstream substrates of GWL: ENSA and ARPP19, suggesting that GWL acts in this pathway in a non-canonical way. Taken together, this thesis presents the discovery of a novel biological pathway in the control of the G1/S transition that could be exploited in cancer therapy to treat TNBC patients.

Item Type: Thesis (Doctoral)
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology Including cancer and carcinogens > RC0270.8 Therapeutics
Depositing User: Library Cataloguing
Date Deposited: 24 Jun 2019 10:09
Last Modified: 28 Jul 2020 07:47
URI: http://sro.sussex.ac.uk/id/eprint/84235

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