ArticleProceedings of the National Academy of Sciences of the United States of America2018
Inhibition of GCN2 sensitizes ASNS-low cancer cells to asparaginase by disrupting the amino acid response.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 119 papers.
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Who cites it
119 citing papers in PubMed, 164 citations in OpenAlex.
- Trial
- White matter disorders at the intersection of transcription, RNA processing and translation.Nature reviews. Neurology · 2026Review
- Therapeutic rescue of pathogenic asparaginyl-tRNA synthetase alleles.Molecular therapy. Nucleic acids · 2026Article
- GCN2 in proteostasis: structural logic, signalling networks and disease.The FEBS journal · 2026Review
- Direct pharmacological targeting of asparagine synthetase to overcome resistance to L-asparaginase in ALL therapy.JCI insight · 2026Article
- Article
- An inhibitor of GCN2 and the integrated stress response directly targets ZAK protein kinase to limit cytotoxicity.The Journal of biological chemistry · 2026Article
- A Novel Potent and Selective GCN2 Inhibitor, APL-4098, Has Antileukemic Activity through Dysregulation of Mitochondrial Function.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Article
- The lncRNA DAMER selectively guides mNature cell biology · 2026Article
- Article
- Tumor metabolic adaptation induced by L-asparaginase reveals a vulnerability to PARP1/2 inhibitor in B-cell lymphomas.Nature communications · 2026Article
- Context-dependent translation inhibition as a cancer therapeutic modality.Nature communications · 2026Article
- Activating GCN2 and subsequently the Unfolded Protein Response with the small oral molecule NXP800 delays tumor growth in osteosarcoma.Cell death discovery · 2026Article
- Combine immune checkpoint indoleamine 2,3-dioxygenase 1 knockdown with ferroptosis inducer Erastin/RSL3 accelerates colorectal cancer cell ferroptosis.CytoJournal · 2026Article
- Inhibition of the integrated stress response rescues a histidyl-tRNA synthetase variant associated with Charcot-Marie-Tooth disease.NAR molecular medicine · 2026Article
- Overcoming immunotherapy resistance in breast cancer: a novel strategy by targeting the integrated stress response.Frontiers in cell and developmental biology · 2026Review
- Mechanisms of mTORC1 and GCN2 amino acid sensing pathways in tumorigenesis and metastatic progression (Review).International journal of molecular medicine · 2026Review
- Article
- Autophagy-targeted intervention synergized with pegaspargase: an innovative therapeutic paradigm for pancreatic cancer.Cancer cell international · 2025Article
- RAF inhibitors activate the integrated stress response by direct activation of GCN2.Nature communications · 2025Article
59 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
15 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
General control nonderepressible 2 (GCN2) plays a major role in the cellular response to amino acid limitation. Although maintenance of amino acid homeostasis is critical for tumor growth, the contribution of GCN2 to cancer cell survival and proliferation is poorly understood. In this study, we generated GCN2 inhibitors and demonstrated that inhibition of GCN2 sensitizes cancer cells with low basal-level expression of asparagine synthetase (ASNS) to the antileukemic agent l-asparaginase (ASNase) in vitro and in vivo. We first tested acute lymphoblastic leukemia (ALL) cells and showed that treatment with GCN2 inhibitors rendered ALL cells sensitive to ASNase by preventing the induction of ASNS, resulting in reduced levels of de novo protein synthesis. Comprehensive gene-expression profiling revealed that combined treatment with ASNase and GCN2 inhibitors induced the stress-activated MAPK pathway, thereby triggering apoptosis. By using cell-panel analyses, we also showed that acute myelogenous leukemia and pancreatic cancer cells were highly sensitive to the combined treatment. Notably, basal ASNS expression at protein levels was significantly correlated with sensitivity to combined treatment. These results provide mechanistic insights into the role of GCN2 in the amino acid response and a rationale for further investigation of GCN2 inhibitors for the treatment of cancer.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.