GCN2 (general control nonderepessible 2) is an eIF2α kinase responsible for entirely rewiring the metabolism of cells when they are put under amino acid starvation stress. Recently, there has been renewed interest in GCN2 as a potential oncotarget, with several studies reporting the development of small molecule inhibitors. The foundation of this work is built upon biochemical and cellular data which suggest GCN2 may be aberrantly overexpressed and is responsible for keeping cells on ‘life-support’ while tumours undergo significant nutritional stress during tumorigenesis, allowing cancer stem cells to develop chemotherapeutic resistance. However, most studies which have investigated the role of GCN2 in cancer have been conducted in various cancer model systems, often under a specific set of stresses, mutational backgrounds and drug cocktails. This review aims to comprehensively summarise the biochemical, molecular and cellular literature associated with GCN2 and its role in various cancers and determine whether a consensus can be developed to discern under which circumstances we may wish to target GCN2.

Background: 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. Method: 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. Results: We observed that the expression levels of GCN2 correlated with patient survival and was an independent prognostic variable in pairwise comparison comparisons with all available clinical data. Conclusion: 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.

Background 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. Methods 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. Results 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. Conclusion 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.