title: Mesenchymal phenotype predisposes lung cancer cells to impaired proliferation and redox stress in response to glutaminase inhibition.
abstract: Recent work has highlighted glutaminase (GLS) as a key player in cancer cell metabolism, providing glutamine-derived carbon and nitrogen to pathways that support proliferation. There is significant interest in targeting GLS for cancer therapy, although the gene is not known to be mutated or amplified in tumors. As a result, identification of tractable markers that predict GLS dependence is needed for translation of GLS inhibitors to the clinic. Herein we validate a small molecule inhibitor of GLS and show that non-small cell lung cancer cells marked by low E-cadherin and high vimentin expression, hallmarks of a mesenchymal phenotype, are particularly sensitive to inhibition of the enzyme. Furthermore, lung cancer cells induced to undergo epithelial to mesenchymal transition (EMT) acquire sensitivity to the GLS inhibitor. Metabolic studies suggest that the mesenchymal cells have a reduced capacity for oxidative phosphorylation and increased susceptibility to oxidative stress, rendering them unable to cope with the perturbations induced by GLS inhibition. These findings elucidate selective metabolic dependencies of mesenchymal lung cancer cells and suggest novel pathways as potential targets in this aggressive cancer type.
authors.affiliation: Agios Pharmaceuticals, Cambridge, Massachusetts, United States of America.
authors.forename: Danielle B
authors.initials: DB
authors.lastname: Ulanet
authors.affiliation: Agios Pharmaceuticals, Cambridge, Massachusetts, United States of America.
authors.forename: Kiley
authors.initials: K
authors.lastname: Couto
authors.affiliation: Agios Pharmaceuticals, Cambridge, Massachusetts, United States of America.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Jha
authors.affiliation: Agios Pharmaceuticals, Cambridge, Massachusetts, United States of America.
authors.forename: Sung
authors.initials: S
authors.lastname: Choe
authors.affiliation: Agios Pharmaceuticals, Cambridge, Massachusetts, United States of America.
authors.forename: Amanda
authors.initials: A
authors.lastname: Wang
authors.affiliation: Agios Pharmaceuticals, Cambridge, Massachusetts, United States of America.
authors.forename: Hin-Koon
authors.initials: HK
authors.lastname: Woo
authors.affiliation: Agios Pharmaceuticals, Cambridge, Massachusetts, United States of America.
authors.forename: Mya
authors.initials: M
authors.lastname: Steadman
authors.affiliation: Agios Pharmaceuticals, Cambridge, Massachusetts, United States of America.
authors.forename: Byron
authors.initials: B
authors.lastname: DeLaBarre
authors.affiliation: Agios Pharmaceuticals, Cambridge, Massachusetts, United States of America.
authors.forename: Stefan
authors.initials: S
authors.lastname: Gross
authors.affiliation: Agios Pharmaceuticals, Cambridge, Massachusetts, United States of America.
authors.forename: Edward
authors.initials: E
authors.lastname: Driggers
authors.affiliation: Agios Pharmaceuticals, Cambridge, Massachusetts, United States of America.
authors.forename: Marion
authors.initials: M
authors.lastname: Dorsch
authors.affiliation: Agios Pharmaceuticals, Cambridge, Massachusetts, United States of America.
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Hurov
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition; D056726:Genetic Association Studies; D005972:Glutaminase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D058990:Molecular Targeted Therapy; D018384:Oxidative Stress / Q000187:drug effects*; D013440:Sulfides / Q000494:pharmacology*; D013830:Thiadiazoles / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D013440:Sulfides; D013830:Thiadiazoles; C523193:bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide; C579480:GLS protein, human; D005972:Glutaminase