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Identification of novel therapeutic approaches for the treatment of tumours characterised by mutations in the Retinoblastoma tumour suppressor gene (RB1)

Mancusi, Caterina; (2021) Identification of novel therapeutic approaches for the treatment of tumours characterised by mutations in the Retinoblastoma tumour suppressor gene (RB1). Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Retinoblastoma protein (RB1) is an important tumour suppressor, which initially has been discovered for its crucial role in the control of cell growth and cell cycle progression. Since then, RB1 has been shown to regulate a plethora of cellular events, including the maintenance of chromosomal stability and DNA repair. Current chemotherapeutic strategies are specifically effective in cancers harbouring deficiencies in DNA repair pathways exploiting a vulnerability of these cancers. In particular genotoxic agents have been shown to induce tumour cell death in DNA damage repair deficient cancers. Inhibitors of the ataxia telangiectasia and Rad3-related protein kinase (ATR) are currently being evaluated in clinical trials as monotherapy as well as in combination with inhibitors of poly(ADP-ribose) polymerases (PARPs), DNA-damaging chemotherapy or radiotherapy. It has been shown that tumours defective in ataxia-telangiectasia mutated (ATM) kinase, display an increased dependency on ATR signalling, and that a combined inactivation of ATM and ATR leads to synthetic lethality. This opens an important question of whether other molecular features in cancers could serve as predictive biomarkers for ATR inhibitor sensitivity. The data presented herein shows that deleterious mutations of RB1 result in hypersensitivity to multiple clinically relevant ATR inhibitors. RB1-mutant cancer cell lines display a significantly enhanced cell death following ATR inhibitor treatment compared to RB1 wild type cancer cell lines. These results were confirmed in RB1 knockout cell lines, proving that RB1 deficiency is the cause of the observed ATR inhibitor sensitivity in RB1 defective cancers. Additionally, RB1-mutant cells display features of DNA replication stress, which were exacerbated following ATR inhibition and exhibit the inability to stabilise stalled replication forks under replication stress inducing agents. These observations could provide a mechanistic explanation for the observed ATR inhibitor sensitivity caused by RB1 loss. Data obtained in this thesis documents a link between RB1 status and ATR inhibitor sensitivity and arguments that cancer types harbouring RB1 mutations should be considered in the design of clinical trials involving ATR inhibitors.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Identification of novel therapeutic approaches for the treatment of tumours characterised by mutations in the Retinoblastoma tumour suppressor gene (RB1)
Event: University College London
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2021. 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 Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
URI: https://discovery.ucl.ac.uk/id/eprint/10120288
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