GCN2: roles in tumour development and progression

Abstract

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.

Targeting c‐Myc transactivation by LMNA inhibits tRNA processing essential for malate‐aspartate shuttle and tumour progression

“…In human cells, there are two major regulatory mechanisms for amino acid sensing, including GCN2 and mTOR signalling pathways 21 . In response to decreased amino acid levels or inhibited ARSs, GCN2 kinase binds tightly to uncharged tRNA to stimulate its autophosphorylation, resulting in up‐regulation of ATF4 to induce gene expression essential for amino acid metabolism 22 . Inhibition of EPRS significantly stimulates GCN2 phosphorylation, which is abrogated by proline 11 .…”

Pilot clinical trial and phenotypic analysis in chemotherapy-pretreated, metastatic triple-negative breast cancer patients treated with oral TAK-228 and TAK-117 (PIKTOR) to increase DNA damage repair deficiency followed by cisplatin and nab paclitaxel

“…This inhibition of protein production allows the cell to upregulate autophagy or modulate other feedback loops to maintain homeostasis. Increased GCN2 levels have been shown to promote immunologic tolerance, thus making immunotherapy ineffective or less effective (41,59,60). Our results suggest that the responders' cancers were not able or as e cient at upregulating stress responses and thus the tumor cells were more susceptible to cell death under metabolic stress.…”

“…53BP1, DAG Lipase β, GCN2, AKT Ser473, and PKCzeta Thr410/403 were decreased in the microdissected tumor specimens metastatic to lymph node (patients 1, 6, and 8) post-PIKTOR. 53BP1 and AKT Ser473 help drive DNA repair (39,40) while GCN2 reduction prevents cells from upregulating metabolic stress responses (41). DAG Lipase β activity is increased in macrophages and immune cells (42,43).…”

Patient-specific and gene-corrected induced pluripotent stem cell-derived endothelial cells elucidate single-cell phenotype of pulmonary veno-occlusive disease

“…Hence, it was not fully convincing to explain why pulmonary vessels were more susceptible to EIF2AK4 mutations. GCN2 is an eIF2α kinase responsible for entirely rewiring the metabolism of cells in response to amino acid starvation stress, and it has been demonstrated that >10% of cancer cell lines appear to be dependent on GCN2 ( Saavedra-García et al., 2021 ) ( Gold and Masson, 2022 ). The factors in the lung environment that trigger the disease require further longitudinal studies.…”