Novel approaches for targeting BRCA2-deficient tumour cells

Thesis

Defects in homologous recombination (HR) repair are associated with significant mortality and improved therapies for HR-deficient tumours are therefore urgently needed. This work aimed to address this unmet need and utilised pharmacological approaches to investigate several methods for the targeting of BRCA2-deficient tumour cells. Parallel lines of investigation demonstrated the selective and effective targeting of BRCA2-deficient cells via both chemical G-quadruplex stabilisation and ERK inhibition. These studies provide impetus for the further development of specific and clinically relevant inhibitors. Further, pharmacological screens generated a body of data relevant to the selective targeting of BRCA2-deficiency. In particular, screening studies demonstrated that targeting the kinase GSK3 selectively kills BRCA2-deficient cells. Moreover, pharmacological screens revealed for the first time that disulfiram, an aldehyde dehydrogenase inhibitor currently in clinical use as an alcohol-aversive agent, induces replicative stress and DNA damage, selectively reducing the viability of BRCA2-deficient human tumour cells. Together, these data reveal a greater dependency of BRCA2-deficient human tumour cells on certain pro-proliferative pathways than their wild type counterparts and demonstrate the vulnerability of BRCA2-deficient cells to replicative stress. Importantly, this work delivers clear rationale for the further study and clinical development of several novel approaches relevant to the treatment of HR-deficient tumours and thus has the potential to help reduce the burden of these devastating diseases in the future.

Authors: Tacconi, E

• DOI: 10.5287/ora-2rey6oyyk
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: BRCA2; BRCA2-deficient tumours; HR-deficient tumours; Targeted cancer therapies