ArticleNature2017
Genomic deletion of malic enzyme 2 confers collateral lethality in pancreatic cancer.
Article in Nature, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 165 papers.
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Who cites it
165 citing papers in PubMed, 264 citations in OpenAlex.
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- Blocking mitochondrial leucine transamination enhances T-cell activation and improves T-cell immunity against OVA-producing EL4 lymphoma.British journal of cancer · 2026Article
- Synthetic lethality targets in pancreatic ductal adenocarcinoma: prevalence and limitations of liquid biopsy detection in a minority-serving cancer center.Future oncology (London, England) · 2026Article
- A loss of the cytosolic branched-chain aminotransferase, BCATc, enhances TImmunometabolism (Cobham, Surrey) · 2026Article
- The aberration of key amino acids participated one-carbon metabolism may jeopardize genetic stability in cancer development.Cell communication and signaling : CCS · 2026Review
- Coenzyme A is a redox sensing cofactor for malic enzyme 2 regulating oxidative stress and mitochondrial metabolism.bioRxiv : the preprint server for biology · 2026Article
- Critical Role for Malic Enzymes in MYC-Mediated Cellular Adaptation to Glutamine Depletion.Metabolites · 2026Article
- Metabolic plasticity in pancreatic ductal adenocarcinoma progression and response to treatment.Molecular cancer · 2026Review
- Nonoxidative pentose phosphate pathway regulates CD8Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Oxidative stress as a nexus: Integrating mitophagy and ferroptosis in endometrial carcinogenesis (Review).Oncology letters · 2026Review
- Collateral lethality of NAD kinase in 1p36 deleted tumors drives vulnerability to NAD kinase 2 depletion.BBA advances · 2026Article
- Tumor metabolic plasticity in therapy resistance: from the Warburg effect to mitochondrial hijacking.Theranostics · 2026Review
- Branched-chain amino acid transaminases as promising targets in tumor therapy.Frontiers in cell and developmental biology · 2026Review
- Passenger co-deletion confounds glutaminolysis signatures anchored on PTEN loss: A cautionary case for location-aware signature design.PloS one · 2026Article
- Collateral metabolic vulnerabilities unveiled by loss of isozyme diversity in breast cancer.Genome medicine · 2025Article
- CYP4F11 promotes lung cancer progression through the miR-195/ME2 pathway.Frontiers of medicine · 2025Article
- Developing a novel TaqMan qPCR assay for optimizingThe veterinary quarterly · 2025Article
- Comprehensive investigation of the molecular basis of cancer dependencies suggests therapeutic options for breast cancer.Cancer biology & medicine · 2025Article
- Article
- Incomplete paralog compensation generates selective dependency on TRA2A in cancer.PLoS genetics · 2025Article
105 more citing papers are in PubMed but not listed here.
Corrections and comments
- Commented on by
- Erratum issued
Authors and funding
25 authors at 2 institutions in 1 country.
Funding
Abstract
The genome of pancreatic ductal adenocarcinoma (PDAC) frequently contains deletions of tumour suppressor gene loci, most notably SMAD4, which is homozygously deleted in nearly one-third of cases. As loss of neighbouring housekeeping genes can confer collateral lethality, we sought to determine whether loss of the metabolic gene malic enzyme 2 (ME2) in the SMAD4 locus would create cancer-specific metabolic vulnerability upon targeting of its paralogous isoform ME3. The mitochondrial malic enzymes (ME2 and ME3) are oxidative decarboxylases that catalyse the conversion of malate to pyruvate and are essential for NADPH regeneration and reactive oxygen species homeostasis. Here we show that ME3 depletion selectively kills ME2-null PDAC cells in a manner consistent with an essential function for ME3 in ME2-null cancer cells. Mechanistically, integrated metabolomic and molecular investigation of cells deficient in mitochondrial malic enzymes revealed diminished NADPH production and consequent high levels of reactive oxygen species. These changes activate AMP activated protein kinase (AMPK), which in turn directly suppresses sterol regulatory element-binding protein 1 (SREBP1)-directed transcription of its direct targets including the BCAT2 branched-chain amino acid transaminase 2) gene. BCAT2 catalyses the transfer of the amino group from branched-chain amino acids to α-ketoglutarate (α-KG) thereby regenerating glutamate, which functions in part to support de novo nucleotide synthesis. Thus, mitochondrial malic enzyme deficiency, which results in impaired NADPH production, provides a prime 'collateral lethality' therapeutic strategy for the treatment of a substantial fraction of patients diagnosed with this intractable disease.
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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.