Novel targets for increasing radiosensitivity in hypoxic tumours

Thesis

Radiotherapy resistance remains a major barrier to durable responses within solid tumours, particularly within lung and colorectal cancers, where hypoxia limits treatment efficacy. Dyskerin pseudouridine synthase 1 (DKC1) is frequently overexpressed in these cancers; its implication in ribosome biogenesis, telomerase activity, and stress signalling suggesting a potential role in increasing tumour radioresistance. This study examined the consequences of DKC1 inhibition using the pharmacological inhibitor Pyrazofurin and siRNA-mediated DKC1 depletion in A549 lung and HCT116 colorectal cancer cell lines. Assays of cell viability, stress signalling, DNA damage, and cell cycle distribution were examined in addition to clonogenic survival following irradiation under normoxia and radiobiological hypoxia (<0.1% 0₂). Pyrazofurin treatment had variable and modest reductions in viability, activated p53 stress responses, and redistributed cells away from G2/M without inducing DNA damage. Importantly, Pyrazofurin sensitised A549 cells to irradiation under normoxia, but this effect was completely abrogated under hypoxia, highlighting the dominant role of oxygen availability in radiosensitivity. These findings establish DKC1 inhibition as an oxygen-dependent modulator of radiosensitivity. As Pyrazofurin itself has limited clinical application due to historical toxicity, and its radiosensitising activity is oxygen dependent, its use in terms of further study does not have a strong case; however, there are avenues of research, such as looking at effects within mild hypoxia, which are yet to be explored.

Authors: Beattie, M

• DOI: 10.5287/ora-z6nxgxjv1
• Type of award: MSc by Research
• Level of award: Masters
• Awarding institution: University of Oxford
• Language: English
• Keywords: Hypoxia Radiotherapy pyrazofurin
• Subjects: Oncology; Tumors