ArticleThe Journal of clinical investigation2021
Guanosine triphosphate links MYC-dependent metabolic and ribosome programs in small-cell lung cancer.
Article in The Journal of clinical investigation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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Who cites it
57 citing papers in PubMed, 74 citations in OpenAlex.
- PTEN-loss confers dependence on the guanylate synthesis enzyme IMPDH in T-cell acute lymphoblastic leukemia.EMBO molecular medicine · 2026Article
- GTP biosynthesis is a therapeutic vulnerability in Rac1-mutant melanoma.bioRxiv : the preprint server for biology · 2026Article
- Nucleotide Metabolism in Health and Disease.MedComm · 2026Review
- Inhibition of ADSS2-mediated de novo AMP biosynthesis re-sensitizes acute myeloid leukemia to BH3 mimetics.Nature cancer · 2026Article
- IMP metabolic mechanisms and IMPDH targeting strategies in tumor metabolic reprogramming and therapy (Review).International journal of molecular medicine · 2026Review
- Targeted metabolism creates possibilities for lung cancer treatment in the precision tumor era.Respiratory research · 2026Review
- Targeting mTOR in Systemic Lupus Erythematosus: From Immune Cell Dysfunction to Clinical Translation.Journal of inflammation research · 2026Review
- PTEN-loss confers dependence on the guanylate synthesis enzyme IMPDH in T-cell acute lymphoblastic leukemia.bioRxiv : the preprint server for biology · 2025Article
- GBP2 condensates promote ferroptosis to sensitize anti-PD-L1 immunotherapy in melanoma.Nature communications · 2025Article
- A Novel Allosteric Inhibitor Targeting IMPDH at Y233 Overcomes Resistance to Tyrosine Kinase Inhibitors in Lymphoma.Cancers · 2025Article
- Tumor-educated platelet RNA as a diagnostic biomarker for ground-glass opacity-related lung adenocarcinoma.Translational lung cancer research · 2025Article
- Nrf2 deficiency enhances oxidative stress and promotes susceptibility to tinnitus in mice.Scientific reports · 2025Article
- Mapping the landscape of metabolic reprogramming research in lung cancer: a bibliometric and visualized analysis.Discover oncology · 2025Article
- Current and future therapies for small cell lung carcinoma.Journal of hematology & oncology · 2025Review
- IMPDH inhibitors upregulate PD-L1 in cancer cells without impairing immune checkpoint inhibitor efficacy.Acta pharmacologica Sinica · 2025Article
- Unveiling the powerhouse: ASCL1-driven small cell lung cancer is characterized by higher numbers of mitochondria and enhanced oxidative phosphorylation.Cancer & metabolism · 2025Article
- Targeting FOXP1 phase separation in small cell lung cancer mechanisms of chemotherapy resistance.Communications biology · 2025Article
- GTPase GPN3 facilitates cell proliferation and migration in non-small cell lung cancer by impeding clathrin-mediated endocytosis of EGFR.Cell death discovery · 2025Article
- Lessons from the physiological role of guanosine in neurodegeneration and cancer: Toward a multimodal mechanism of action?Purinergic signalling · 2025Review
- Fuel for thought: targeting metabolism in lung cancer.Translational lung cancer research · 2024Review
Corrections and comments
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Authors and funding
28 authors at 7 institutions in 3 countries.
Funding
Abstract
MYC stimulates both metabolism and protein synthesis, but how cells coordinate these complementary programs is unknown. Previous work reported that, in a subset of small-cell lung cancer (SCLC) cell lines, MYC activates guanosine triphosphate (GTP) synthesis and results in sensitivity to inhibitors of the GTP synthesis enzyme inosine monophosphate dehydrogenase (IMPDH). Here, we demonstrated that primary MYChi human SCLC tumors also contained abundant guanosine nucleotides. We also found that elevated MYC in SCLCs with acquired chemoresistance rendered these otherwise recalcitrant tumors dependent on IMPDH. Unexpectedly, our data indicated that IMPDH linked the metabolic and protein synthesis outputs of oncogenic MYC. Coexpression analysis placed IMPDH within the MYC-driven ribosome program, and GTP depletion prevented RNA polymerase I (Pol I) from localizing to ribosomal DNA. Furthermore, the GTPases GPN1 and GPN3 were upregulated by MYC and directed Pol I to ribosomal DNA. Constitutively GTP-bound GPN1/3 mutants mitigated the effect of GTP depletion on Pol I, protecting chemoresistant SCLC cells from IMPDH inhibition. GTP therefore functioned as a metabolic gate tethering MYC-dependent ribosome biogenesis to nucleotide sufficiency through GPN1 and GPN3. IMPDH dependence is a targetable vulnerability in chemoresistant MYChi SCLC.
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