The integrated stress response kinase general control non-derepressible 2 (GCN2) is a novel prognostic biomarker and therapeutic target in malignant pleural mesothelioma

Abstract

Malignant pleural mesothelioma (MPM) is a cancer of the mesothelial cells of the pleural cavity, with a five-year survival rate of five percent and extremely limited treatment options with poor response rates. Previous work identified the transcription factor C/EBP homologous protein (CHOP) as a prognostic biomarker in MPM. CHOP levels are also associated with the amino acid response (AAR) arm of the integrated stress response (ISR), mediated by nutrient stress sensing kinase general control non-derepressible 2 (GCN2). GCN2 activity is hijacked in multiple cancers to overcome nutrient starvation associated with tumorigenesis, and both inhibiting and activating compounds have shown promising results as potential new therapeutics. This work immunohistochemically stained MPM tumour samples for GCN2 and determined whether levels were associated with patient prognosis. GCN2 levels were associated with worse patient prognoses and was also a predictive factor for one-year outcomes. GCN2 may therefore prove a useful staining target to determine prognosis in MPM patients. Additionally, the correlation between high GCN2 levels and worse patient prognoses suggests that GCN2 levels are associated with more aggressive cancer and identifies a potential weakness in MPM tumours that could be exploited therapeutically.

Date of Award	2023
Original language	English
Awarding Institution	University of Dundee
Supervisor	Glenn Masson (Supervisor) & Russell Petty (Supervisor)