title: Genomic deletion of malic enzyme 2 confers collateral lethality in pancreatic cancer.
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.
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Prasenjit
authors.initials: P
authors.lastname: Dey
authors.affiliation: Department of Chemical and Biomolecular Engineering, Department of Bioengineering, Rice University, 6100 Main Street, Houston, Texas 77005, USA.
authors.forename: Joelle
authors.initials: J
authors.lastname: Baddour
authors.affiliation: Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Florian
authors.initials: F
authors.lastname: Muller
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Chia Chin
authors.initials: CC
authors.lastname: Wu
authors.affiliation: Department of Pathology, Division of Pathology/Lab Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Huamin
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Wen-Ting
authors.initials: WT
authors.lastname: Liao
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Zangdao
authors.initials: Z
authors.lastname: Lan
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Alina
authors.initials: A
authors.lastname: Chen
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Tony
authors.initials: T
authors.lastname: Gutschner
authors.affiliation: Department of Surgical Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Yaan
authors.initials: Y
authors.lastname: Kang
authors.affiliation: Department of Surgical Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Fleming
authors.affiliation: Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Nikunj
authors.initials: N
authors.lastname: Satani
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Di
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Department of Chemical and Biomolecular Engineering, Department of Bioengineering, Rice University, 6100 Main Street, Houston, Texas 77005, USA.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Achreja
authors.affiliation: Department of Chemical and Biomolecular Engineering, Department of Bioengineering, Rice University, 6100 Main Street, Houston, Texas 77005, USA.
authors.forename: Lifeng
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Chemical and Biomolecular Engineering, Department of Bioengineering, Rice University, 6100 Main Street, Houston, Texas 77005, USA.
authors.forename: Jiyoon
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Chang
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Giannicola
authors.initials: G
authors.lastname: Genovese
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Viale
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Haoqiang
authors.initials: H
authors.lastname: Ying
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Giulio
authors.initials: G
authors.lastname: Draetta
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Sheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Y Alan
authors.initials: YA
authors.lastname: Wang
authors.affiliation: Department of Chemical and Biomolecular Engineering, Department of Bioengineering, Rice University, 6100 Main Street, Houston, Texas 77005, USA.
authors.forename: Deepak
authors.initials: D
authors.lastname: Nagrath
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Ronald A
authors.initials: RA
authors.lastname: DePinho
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000597:Amino Acids, Branched-Chain / Q000378:metabolism; D000818:Animals; D055162:Biocatalysis; D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology / Q000235:genetics* / Q000523:psychology / Q000628:therapy; D017353:Gene Deletion; D006801:Humans; D007656:Ketoglutaric Acids / Q000378:metabolism; D008291:Malate Dehydrogenase / Q000172:deficiency* / Q000235:genetics; D008297:Male; D051379:Mice; D015778:Minor Histocompatibility Antigens / Q000096:biosynthesis / Q000235:genetics; D008928:Mitochondria / Q000201:enzymology / Q000473:pathology; D009249:NADP / Q000096:biosynthesis / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D011257:Pregnancy Proteins / Q000096:biosynthesis / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D000637:Transaminases / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000597:Amino Acids, Branched-Chain; D007656:Ketoglutaric Acids; D015778:Minor Histocompatibility Antigens; D011257:Pregnancy Proteins; D017382:Reactive Oxygen Species; D051780:Sterol Regulatory Element Binding Protein 1; D009249:NADP; D008291:Malate Dehydrogenase; C495394:malic enzyme 2; human; D000637:Transaminases; C424463:BCAT2 protein, human; D055372:AMP-Activated Protein Kinases