THE ROLE OF THE P53 TUMOUR SUPPRESSOR GENE IN CANCER DEVELOPMENT AND TREATMENT

Abstract

Genetic alterations grant cancer cells adaptive advantages, enabling them to survive the hostile microenvironment induced by anticancer therapies and relapse with a more aggressive phenotype— posing a significant challenge in oncology. At the forefront of these genetic regulators is the tumour suppressor gene p53, one of the most extensively studied in cancer research for its pivotal role in mediating cellular responses to treatment and regulating metabolic pathways that drive therapeutic resistance. However, the precise mechanisms by which p53 orchestrates these processes and interacts with other key regulatory networks remain incompletely understood. Building on existing experimental data, this thesis develops novel mathematical frameworks, modelling p53 dynamics in response to the chemotherapeutic agent Doxorubicin (Dox) and its role in cancer metabolism. By analysing these models using mathematical techniques and examining different scenarios commonly encountered by cancer cells, this work offers a deeper understanding of cancer resistance mechanisms and informs potential therapeutic strategies. Our first study (Chapter 2) investigating cellular responses to Dox treatment reveals that in addition to the variability in p53 dynamics across individual cells that may drive differential treatment outcomes, the heterogeneity in X-linked inhibitor of apoptosis protein (XIAP) induction rate can also play a role by blocking apoptosis even when p53 is highly activated. Expanding beyond its apoptotic function, the second study (Chapter 3) demonstrates how p53 counteracts theWarburg effect—a metabolic adaptation that enhances cancer cell adaptability and apoptosis evasion. This insight emerges from a comprehensive mathematical framework integrating p53 metabolic targets alongside other genetic regulators, accurately capturing experimental observations of glucose metabolism in both wild-type and p53-mutated colon cancer cells. Further exploring these findings, the third study (Chapter 4) provides additional perspectives by incorporating the impact of hypoxia-inducible factor 1 (HIF1) stabilisation following Dox treatment. The results suggest that although higher doses of Dox can trigger cell death more effectively through robust p53 activation, they risk promoting aggressiveness post-treatment if apoptosis is not successfully induced. Together, by integrating the apoptotic and metabolic roles of p53, this work highlights the importance of its functionality in overcoming therapeutic resistance, along with XIAP and HIF1 activation mechanisms, suggesting them as potential co-targets to increase cellular sensitivity and minimise the risk of relapse.