title: mTORC1-Dependent Metabolic Reprogramming Underlies Escape from Glycolysis Addiction in Cancer Cells.
abstract: Although glycolysis is substantially elevated in many tumors, therapeutic targeting of glycolysis in cancer patients has not yet been successful, potentially reflecting the metabolic plasticity of tumor cells. In various cancer cells exposed to a continuous glycolytic block, we identified a recurrent reprogramming mechanism involving sustained mTORC1 signaling that underlies escape from glycolytic addiction. Active mTORC1 directs increased glucose flux via the pentose phosphate pathway back into glycolysis, thereby circumventing a glycolysis block and ensuring adequate ATP and biomass production. Combined inhibition of glycolysis and mTORC1 signaling disrupted metabolic reprogramming in tumor cells and inhibited their growth in vitro and in vivo. These findings reveal novel combinatorial therapeutic strategies to realize the potential benefit from targeting the Warburg effect.
authors.affiliation: Department of Discovery Oncology, Genentech Inc, South San Francisco, CA 94080, USA.
authors.forename: Raju V
authors.initials: RV
authors.lastname: Pusapati
authors.affiliation: Department of Bioinformatics and Computational Biology, Genentech Inc, South San Francisco, CA 94080, USA.
authors.forename: Anneleen
authors.initials: A
authors.lastname: Daemen
authors.affiliation: Department of Discovery Oncology, Genentech Inc, South San Francisco, CA 94080, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Wilson
authors.affiliation: Department of Protein Chemistry, Genentech Inc, South San Francisco, CA 94080, USA.
authors.forename: Wendy
authors.initials: W
authors.lastname: Sandoval
authors.affiliation: Department of Translational Oncology, Genentech Inc, South San Francisco, CA 94080, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Gao
authors.affiliation: Department of Molecular Biology, Genentech Inc, South San Francisco, CA 94080, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Haley
authors.affiliation: Department of Biomedical Imaging, Genentech Inc, South San Francisco, CA 94080, USA.
authors.forename: Andreas R
authors.initials: AR
authors.lastname: Baudy
authors.affiliation: Department of Translational Oncology, Genentech Inc, South San Francisco, CA 94080, USA.
authors.forename: Georgia
authors.initials: G
authors.lastname: Hatzivassiliou
authors.affiliation: Department of Discovery Oncology, Genentech Inc, South San Francisco, CA 94080, USA. Electronic address: evangelista.marie@gene.com.
authors.forename: Marie
authors.initials: M
authors.lastname: Evangelista
authors.affiliation: Department of Discovery Oncology, Genentech Inc, South San Francisco, CA 94080, USA. Electronic address: settleman@calicolabs.com.
authors.forename: Jeff
authors.initials: J
authors.lastname: Settleman
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D002277:Carcinoma / Q000473:pathology; D045744:Cell Line, Tumor; D002952:Citric Acid Cycle; D003131:Combined Modality Therapy; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000235:genetics; D003847:Deoxyglucose / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004734:Energy Metabolism / Q000187:drug effects; D000068338:Everolimus / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D005956:Glucose-6-Phosphate Isomerase / Q000037:antagonists & inhibitors / Q000235:genetics; D005972:Glutaminase / Q000037:antagonists & inhibitors / Q000502:physiology; D005973:Glutamine / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D055432:Metabolomics; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000502:physiology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000473:pathology; D010427:Pentose Phosphate Pathway / Q000187:drug effects / Q000502:physiology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000627:therapeutic use; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
chemical_list: D016207:Cytokines; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D005973:Glutamine; D000255:Adenosine Triphosphate; D003847:Deoxyglucose; D000068338:Everolimus; D000076222:Mechanistic Target of Rapamycin Complex 1; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; D005972:Glutaminase; C554959:GPI protein, human; D005956:Glucose-6-Phosphate Isomerase