Exploiting Epigenetic Dysregulation in SWI/SNF-Deficient Lung Adenocarcinoma

The Switch/Sucrose Non-Fermentable (SWI/SNF) DNA remodelling complexes regulate gene expression and aberrant SWI/SNF function is associated with epigenetic dysregulation underlying cancer. Recurrent mutations in genes encoding SWI/SNF subunits have been described in >20% of all human malignancies. Lung cancer is the fifth most common cancer diagnosed annually and it’s the highest cause of cancer related death. LUAD makes up to 40% of all lung cancer patients and has a 5-year survival of ~20%, due to the poor efficiency of the current treatment options, including chemotherapy, radiotherapy and immunotherapy, highlighting the urgent need of more targeted therapies. SMARCA4 encodes the core ATPase subunit of the SWI/SNF complex and is mutated in ~8% of lung adenocarcinoma (LUAD) patients. Additionally, a total 37% of LUAD patients exhibit a mutation in one of the 31 SWI/SNF genes and these are largely mutually exclusive from each other. To better understand the mechanism SWI/SNF-mediated epigenetic dysregulation in LUAD, we have performed in vitro CRISPR knockout screens using epigenetic- and druggable target-focused gRNA libraries in SMARCA4 wildtype and SMARCA4-deficient LUAD cell lines. Capitializing on these unique data sets, this project will utilize a range of clinically relevant LUAD models to define novel therapeutic approaches for SWI/SNF-deficient LUAD.