Characterisation of a novel genetically engineered mouse model of non-small cell lung cancer with a dynamic immune response

Lung cancer is the most common form of cancer in the world, both in terms of diagnosis and number of deaths per annum. Approximately 85% of cases diagnosed are non-small cell lung cancer (NSCLC), of which adenocarcinoma is the most common histological subtype. Specific DNA mutations allow for molecular characterisation of the disease and activating mutations in KRAS are present in one third of cases. The oncogene MYC is a downstream target of KRAS and the two proteins have long been known to cooperate with one another to induce tumorigenesis. The gene editing enzyme APOBEC3B (A3B) is a cytidine deaminase, deaminating cytidine residues in the genome, resulting in C > T transversions. If these point mutations occur in the coding region of a gene this can result in a mutated protein with altered function. A3B has been shown to be involved in tumour evolution, invasion and metastasis, making it an attractive target for investigation. Additionally, upregulation of A3B in NSCLC has been correlated with an increase in mutations at GC base pairs and the A3B mutations signature has been noted in the tumours of both smokers and non-smokers. The mutations caused by A3B catalytic activity may result in the tumours being more immune visible, due to increased neoantigen production. This presents an opportunity for the tumour immune response to recognise tumour cells and destroy them before they can progress to a clinically relevant malignancy. Genetically engineered mouse models of cancer have contributed significantly to the field of cancer research. Tumours arising in advanced GEMMs closely mimic the features of their human counterparts and are able to spontaneously progress to metastatic disease. However, there are some limitations to currently available GEMMs, one such being that they are not truly reflective of the high tumour mutation burden seen in human non-small cell lung cancer. Therefore, there is an urgent need to develop models that reflect the mutational diversity seen in the human disease in order to better understand the challenges faced in the human disease, such as resistance to therapy. The work presented in this thesis describes the characterisation of a novel genetically engineered mouse model of NSCLC. This conditional model allows for the expression of the oncogenes Kras and Myc (KM) exclusively in the lung epithelium to drive tumour formation. A modest overexpression of A3B (KMA) is then used to drive increased tumour mutation burden.