Poster Presentation 35th Lorne Cancer Conference 2023

Investigating the roles of mutant TP53 in lung adenocarcinoma using novel genetically engineered mouse models (#122)

Tianwei Chen 1 , Andreas Strasser 1 , Gemma Kelly 1 , Kate Sutherland 1 , Elizabeth Lieschke 1 , Danielle Boyd 1
  1. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia

Lung adenocarcinoma (LUAD) is a highly heterogenous disease that can be divided into different subtypes based on their oncogenic drivers, with activation of KRAS being one of the most frequently mutated genes1. Co-occurring mutations of tumour suppressor genes are frequently observed in KRAS-mutant LUAD and are found to contribute to the molecular and clinical heterogeneity of LUAD2. In particular, inactivation of TP53 is the most common gene mutation found in KRAS-mutant LUAD1.


The transcription factor TP53 (TRP53 in mouse), encoded by the TP53 gene (Trp53 in mouse) is a tumour suppressor that protects cells from malignant transformation by activating various cellular responses, including apoptotic cell death, cellular senescence, cell cycle arrest, DNA damage repair and adaptation of cellular metabolism3. TP53 is mutated in approximately 50% of human cancers and is associated with poor therapeutic responses4. Mutant TP53 promotes tumour development in three ways: (1) loss of function effects (LOF), which abrogate normal TP53-mediated cellular processes, leading to defects in cell cycle control, evasion of apoptosis and genetic instability5; (2) dominant negative effects (DNE) that result from the formation of mixed tetramers containing both wild-type (WT) and mutant TP53 whereby such mixed tetramers cannot activate the WT TP53 target genes3; and (3) gain of function effects (GOF) that are thought to be exerted by binding to and modulating the functions of other transcription factors4,6. In this project, we aim to examine the relative importance of these processes in the development and sustained expansion of LUAD using novel mouse models that permit the inducible expression of mutant Trp53 to trigger tumorigenesis and conversion of the mutant Trp53 either back to WT or into a Trp53 knock-out state in tumour cells. Our preliminary data suggest that conversion of mutant Trp53 back to WT Trp53 can induce cellular senescence and cell cycle arrest in KRAS mutant, Trp53 mutant LUAD cells in vitro, whereas conversion of mutant Trp53 to Trp53 knock-out does not impair the sustained growth of these malignant cells. Our innovative mouse models will allow us to interrogate with precision, the importance of mutant TP53 in the initiation and sustained growth of LUAD.