Abstract LT06: Understanding the Role of Mutant TP53 in Lung Cancer Using Novel Genetically Engineered Mouse Models

Abstract The tumour suppressor gene TP53 (Trp53 in mouse) is mutated in ~50% of human cancers and this is associated with poor therapeutic responses. Mutant TP53 protein was reported to promote tumour development in three ways: (1) loss of function (LOF) effects which abrogate normal TP53-mediated cellular processes; (2) dominant negative effects (DNE) ; and (3) gain of function effects (GOF) whereby mutant TP53 proteins bind to and modulate the functions of proteins that are not impacted by wildtype TP53. Despite extensive research efforts, the relative contributions of the LOF, DNE and GOF effects of mutant TP53 in cancer are largely unknown. This project aims to understand the relative importance of these three effects of TP53 mutant proteins in the initiation and sustained expansion of lung adenocarcinoma (LUAD). We will do this by using novel LUAD mouse models with switchable Trp53 status to trigger tumorigenesis through expression of mutant Trp53 and then conversion of mutant Trp53 either back to wildtype Trp53 or into a Trp53 knock-out state when desired. In vitro and in vivo studies were performed to investigate the immediate and long-term effects of different Trp53 status on tumour growth. Our data thus far show that conversion of mutant Trp53 back to wildtype Trp53 induced cellular senescence and cell cycle arrest in LUAD cells in vitro and substantially delayed tumour progression in vivo, which improved the overall survival of mice. In contrast, conversion of mutant Trp53 into a Trp53 knock-out state did not impair the sustained growth of these tumour cells either in vitro or in vivo. This suggest that the LOF but not GOF of mutant TRP53 is critical to sustain the expansion of lung cancer. These findings have important implications for the design of novel therapeutic approaches for cancers expressing mutant TP53. Citation Format: Tianwei Chen, Elizabeth Lieschke, Leanne Scott, Danielle Boyd, Kate Sutherland, Andreas Strasser, Gemma Kelly. Understanding the Role of Mutant TP53 in Lung Cancer Using Novel Genetically Engineered Mouse Models abstract. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84 (8Suppl): Abstract nr LT06.