title: mTORC1-Driven Tumor Cells Are Highly Sensitive to Therapeutic Targeting by Antagonists of Oxidative Stress.
abstract: mTORC1 is a central signaling node in controlling cell growth, proliferation, and metabolism that is aberrantly activated in cancers and certain cancer-associated genetic disorders, such as tuberous sclerosis complex (TSC) and sporadic lymphangioleiomyomatosis. However, while mTORC1-inhibitory compounds (rapamycin and rapalogs) attracted interest as candidate therapeutics, clinical trials have not replicated the promising findings in preclinical models, perhaps because these compounds tend to limit cell proliferation without inducing cell death. In seeking to address this issue, we performed a high-throughput screen for small molecules that could heighten the cytotoxicity of mTORC1 inhibitors. Here we report the discovery that combining inhibitors of mTORC1 and glutamate cysteine ligase (GCLC) can selectively and efficiently trigger apoptosis in Tsc2-deficient cells but not wild-type cells. Mechanistic investigations revealed that coinhibition of mTORC1 and GCLC decreased the level of the intracellular thiol antioxidant glutathione (GSH), thereby increasing levels of reactive oxygen species, which we determined to mediate cell death in Tsc2-deficient cells. Our findings offer preclinical proof of concept for a strategy to selectively increase the cytotoxicity of mTORC1 inhibitors as a therapy to eradicate tumor cells marked by high mTORC1 signaling, based on cotargeting a GSH-controlled oxidative stress pathway. Cancer Res; 76(16); 4816-27. ©2016 AACR.
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Meyer Cancer Center, Weill Cornell Medicine, New York, New York.
authors.forename: Sejeong
authors.initials: S
authors.lastname: Shin
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. Department of Dermatology, Massachusetts General Hospital, Charlestown, Massachusetts.
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Pharmacology, Meyer Cancer Center, Weill Cornell Medicine, New York, New York.
authors.forename: Sang-Oh
authors.initials: SO
authors.lastname: Yoon
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, Massachusetts. Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Chenggang
authors.initials: C
authors.lastname: Li
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, Massachusetts. Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Erik
authors.initials: E
authors.lastname: Zhang
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, Massachusetts. Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Jane
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Dermatology, Massachusetts General Hospital, Charlestown, Massachusetts.
authors.forename: Jianming
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts. Department of Pharmacology, Meyer Cancer Center, Weill Cornell Medicine, New York, New York. job2064@med.cornell.edu.
authors.forename: John
authors.initials: J
authors.lastname: Blenis
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D055785:Gene Knockdown Techniques; D057166:High-Throughput Screening Assays; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D016513:Mice, SCID; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors*; D018384:Oxidative Stress / Q000187:drug effects*; D016133:Polymerase Chain Reaction; D017382:Reactive Oxygen Species; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D046912:Multiprotein Complexes; D017382:Reactive Oxygen Species; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus