title: Translation initiation factor eIF4F modifies the dexamethasone response in multiple myeloma.
abstract: Enhanced protein synthesis capacity is associated with increased tumor cell survival, proliferation, and resistance to chemotherapy. Cancers like multiple myeloma (MM), which display elevated activity in key translation regulatory nodes, such as the PI3K/mammalian target of rapamycin and MYC-eukaryotic initiation factor (eIF) 4E pathways, are predicted to be particularly sensitive to therapeutic strategies that target this process. To identify novel vulnerabilities in MM, we undertook a focused RNAi screen in which components of the translation apparatus were targeted. Our screen was designed to identify synthetic lethal relationships between translation factors or regulators and dexamethasone (DEX), a corticosteroid used as frontline therapy in this disease. We find that suppression of all three subunits of the eIF4F cap-binding complex synergizes with DEX in MM to induce cell death. Using a suite of small molecules that target various activities of eIF4F, we observed that cell survival and DEX resistance are attenuated upon eIF4F inhibition in MM cell lines and primary human samples. Levels of MYC and myeloid cell leukemia 1, two known eIF4F-responsive transcripts and key survival factors in MM, were reduced upon eIF4F inhibition, and their independent suppression also synergized with DEX. Inhibition of eIF4F in MM exerts pleotropic effects unraveling a unique therapeutic opportunity.
authors.affiliation: Departments of Biochemistry.
authors.forename: Francis
authors.initials: F
authors.lastname: Robert
authors.affiliation: Medicine and Hematology, and.
authors.forename: William
authors.initials: W
authors.lastname: Roman
authors.affiliation: The Rosalind and Morris Goodman Cancer Research Center, McGill University, Montreal, QC, Canada H3G 1Y6;
authors.forename: Alexandre
authors.initials: A
authors.lastname: Bramoullé
authors.affiliation: Mirimus, Inc., Cold Spring Harbor, NY 11724; and.
authors.forename: Christof
authors.initials: C
authors.lastname: Fellmann
authors.affiliation: The Rosalind and Morris Goodman Cancer Research Center, McGill University, Montreal, QC, Canada H3G 1Y6;
authors.forename: Anne
authors.initials: A
authors.lastname: Roulston
authors.affiliation: Medicine and Hematology, and.
authors.forename: Chaim
authors.initials: C
authors.lastname: Shustik
authors.affiliation: Center for Chemical Methodology and Library Development, Boston University, Boston, MA 02215.
authors.forename: John A
authors.initials: JA
authors.lastname: Porco
authors.affiliation: Departments of Biochemistry, The Rosalind and Morris Goodman Cancer Research Center, McGill University, Montreal, QC, Canada H3G 1Y6;
authors.forename: Gordon C
authors.initials: GC
authors.lastname: Shore
authors.affiliation: Medicine and Hematology, and michael.sebag@mcgill.ca jerry.pelletier@mcgill.ca.
authors.forename: Michael
authors.initials: M
authors.lastname: Sebag
authors.affiliation: Departments of Biochemistry, The Rosalind and Morris Goodman Cancer Research Center, McGill University, Montreal, QC, Canada H3G 1Y6; Oncology, and michael.sebag@mcgill.ca jerry.pelletier@mcgill.ca.
authors.forename: Jerry
authors.initials: J
authors.lastname: Pelletier
mesh_terms: D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000494:pharmacology / Q000627:therapeutic use*; D039562:Eukaryotic Initiation Factor-4F / Q000378:metabolism*; D060045:Genes, Modifier; D006801:Humans; D058990:Molecular Targeted Therapy; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D034622:RNA Interference / Q000187:drug effects; D013489:Suppression, Genetic / Q000187:drug effects; D014315:Triterpenes / Q000494:pharmacology; D001572:Benzofurans
chemical_list: D003907:Dexamethasone; D039562:Eukaryotic Initiation Factor-4F; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016271:Proto-Oncogene Proteins c-myc; D014315:Triterpenes; C579095:MCL1 protein, human; C489897:silvestrol; D001572:Benzofurans
keywords: RNAi screening; eIF4A; hippuristanol; silvestrol