The amino-acid stress sensing eIF2α kinase GCN2 is a survival biomarker for malignant mesothelioma

Abstract

Malignant mesothelioma is a tumour that is strongly associated with a history of asbestos exposure, and which derives from mesothelial cells that line the serous cavities of the body. The tumour most commonly arises in the pleural cavity, but can also arise in the pericardium, peritoneum, and tunica vaginalis. At present the lesion has a very poor prognosis and is an incurable form of cancer with median survival times of up to 19 months being quoted for some histological subtypes. A large proportion of mesotheliomas have been shown to be arginine auxotrophic, leading to new research for therapeutics which might exploit this potential vulnerability. We measured the levels of General Control Non-derepressible 2 (GCN2) protein in malignant mesothelioma tumour samples and determined whether these levels correlate with clinical outcomes. We observed that the expression levels of GCN2 correlated with patient survival and was an independent prognostic variable in pairwise comparisons with all available clinical data. These findings suggest that GCN2 levels provides prognostic information and may allow for stratification of care pathways. It may suggest that targeting GCN2 is a viable strategy for mesothelioma therapy development.