title: Gene expression-based discovery of atovaquone as a STAT3 inhibitor and anticancer agent.
abstract: The oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) is frequently activated inappropriately in a wide range of hematological and solid cancers, but clinically available therapies targeting STAT3 are lacking. Using a computational strategy to identify compounds opposing the gene expression signature of STAT3, we discovered atovaquone (Mepron), an antimicrobial approved by the US Food and Drug Administration, to be a potent STAT3 inhibitor. We show that, at drug concentrations routinely achieved clinically in human plasma, atovaquone inhibits STAT3 phosphorylation, the expression of STAT3 target genes, and the viability of STAT3-dependent hematological cancer cells. These effects were also observed with atovaquone treatment of primary blasts isolated from patients with acute myelogenous leukemia or acute lymphocytic leukemia. Atovaquone is not a kinase inhibitor but instead rapidly and specifically downregulates cell-surface expression of glycoprotein 130, which is required for STAT3 activation in multiple contexts. The administration of oral atovaquone to mice inhibited tumor growth and prolonged survival in a murine model of multiple myeloma. Finally, in patients with acute myelogenous leukemia treated with hematopoietic stem cell transplantation, extended use of atovaquone forPneumocystisprophylaxis was associated with improved relapse-free survival. These findings establish atovaquone as a novel, clinically accessible STAT3 inhibitor with evidence of anticancer efficacy in both animal models and humans.
authors.affiliation: Department of Medical Oncology and.
authors.forename: Michael
authors.initials: M
authors.lastname: Xiang
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: Haesook
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Medical Oncology and.|Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; and.
authors.forename: Vincent T
authors.initials: VT
authors.lastname: Ho
authors.affiliation: Department of Medical Oncology and.|Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; and.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Walker
authors.affiliation: Department of Medical Oncology and.
authors.forename: Michal
authors.initials: M
authors.lastname: Bar-Natan
authors.affiliation: Department of Medical Oncology and.
authors.forename: Melodi
authors.initials: M
authors.lastname: Anahtar
authors.affiliation: Department of Medical Oncology and.
authors.forename: Suhu
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Medical Oncology and.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Toniolo
authors.affiliation: Department of Medical Oncology and.
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Kroll
authors.affiliation: Department of Medical Oncology and.
authors.forename: Nichole
authors.initials: N
authors.lastname: Jones
authors.affiliation: Department of Medical Oncology and.
authors.forename: Zachary T
authors.initials: ZT
authors.lastname: Giaccone
authors.affiliation: Department of Medical Oncology and.
authors.forename: Lisa N
authors.initials: LN
authors.lastname: Heppler
authors.affiliation: Department of Medical Oncology and.
authors.forename: Darwin Q
authors.initials: DQ
authors.lastname: Ye
authors.affiliation: Department of Medical Oncology and.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Marineau
authors.affiliation: Department of Medical Oncology and.
authors.forename: Daniel
authors.initials: D
authors.lastname: Shaw
authors.affiliation: Department of Medical Oncology and.
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: Traci
authors.initials: T
authors.lastname: Blonquist
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.affiliation: Geroscience Center for Brain Health and Metabolism and.|Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile.
authors.forename: Claudio
authors.initials: C
authors.lastname: Hetz
authors.affiliation: Department of Medical Oncology and.|Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; and.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Stone
authors.affiliation: Department of Medical Oncology and.|Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; and.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Soiffer
authors.affiliation: Department of Medical Oncology and.|Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; and.
authors.forename: David A
authors.initials: DA
authors.lastname: Frank
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D053626:Atovaquone / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D055808:Drug Discovery; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D050796:STAT3 Transcription Factor; D050822:Cytokine Receptor gp130; D019000:Phosphotyrosine; D053626:Atovaquone