Lung squamous cell carcinoma (LUSC) is a subtype of non-small cell lung cancer and constitutes around 25% of all lung cancer cases worldwide. Despite recent advancements in cancer therapeutics, no targeted therapies have been approved specifically for LUSC. The lineage- survival oncogene and transcription factor SOX2 is dysregulated by gene amplification in a large proportion of LUSC tumours and has been implicated as a key driver in multiple preclinical functional studies. As a transcription factor, SOX2 itself makes a challenging drug target. New therapeutic approaches are required for this disease, and this project identified and evaluated potential therapeutic targets for SOX2-driven LUSC.

Multi-omics data was used to identify drug target candidates from the SOX2 interactome in LUSC, and ten target candidates were selected for in vitro validation. Targeting the PI3K/AKT/mTOR pathway showed benefits in SOX2-driven disease, and the transcription factor FOXM1 was highlighted as a promising target candidate in SOX2-driven LUSC tumours.

Additionally, transcriptional data of LUSC tumours was used to identify differentially expressed genes in SOX2-high tumours, and identified TrkB (encoded by the NTRK2 gene) as a potential drug target candidate. Expression of TrkB correlated with SOX2 expression in squamous tumours, showed a functional role in squamous cancers, and NTRK2 was confirmed as a transcriptional target of the SOX2 transcription factor. Deregulation of TrkB expression and specific transcript variants showed an impact on cell fitness, survival, and downstream signalling. While TrkB.T1 was shown to be the predominant transcript variant of the NTRK2 gene in LUSC and other squamous cancers, both TrkB.T1 and TrkB.FL variants had a functional role in oncogenic signalling. Targeting TrkB in patients with high SOX2 expression might therefore be a promising strategy for further evaluation in LUSC.

Finally, this project characterised current in vitro models of LUSC and undertook early efforts to develop new models from human bronchial epithelial cells. Better models are needed to study the disease and to test new therapeutics. Ultimately, good in vitro models of LUSC remain a challenge and require future work.

In summary, this project identified a set of drug target candidates in SOX2-driven LUSC and presented in vitro validation results to support the further development of selected targets. This work generated new insights into SOX2 pathobiology in LUSC and contributed to the development of new therapeutic approaches to treat this disease with clear unmet medical needs.