title: Synergistic effects of eIF4A and MEK inhibitors on proliferation of NRAS-mutant melanoma cell lines.
abstract: Activating mutations of the NRAS (neuroblastoma rat sarcoma viral oncogene) protein kinase, present in many cancers, induce a constitutive activation of both the RAS-RAF-MEK-ERK mitogen-activated protein kinase (MAPK) signal transduction pathway and the PI(3)K-AKT-mTOR, pathway. This in turn regulates the formation of the eIF4F eukaryotic translation initiation complex, comprising the eIF4E cap-binding protein, the eIF4G scaffolding protein and the eIF4A RNA helicase, which binds to the 7-methylguanylate cap (m(7)G) at the 5' end of messenger RNAs. Small molecules targeting MEK (MEKi: MEK inhibitors) have demonstrated activity in NRAS-mutant cell lines and tumors, but resistance sets in most cases within months of treatment. Using proximity ligation assays, that allows visualization of the binding of eIF4E to the scaffold protein eIF4G, generating the active eIF4F complex, we have found that resistance to MEKi is associated with the persistent formation of the eIF4F complex in MEKi-treated NRAS-mutant cell lines. Furthermore, inhibiting the eIF4A component of the eIF4F complex, with a small molecule of the flavagline/rocaglate family, synergizes with inhibiting MEK to kill NRAS-mutant cancer cell lines.
authors.affiliation: a INSERM U981 , Villejuif , France.|b Université Paris-Sud , Kremlin-Bicêtre , France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Malka-Mahieu
authors.affiliation: a INSERM U981 , Villejuif , France.|g Gustave Roussy, Dermato-Oncology , Villejuif , France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Girault
authors.affiliation: a INSERM U981 , Villejuif , France.|b Université Paris-Sud , Kremlin-Bicêtre , France.
authors.forename: Margot
authors.initials: M
authors.lastname: Rubington
authors.affiliation: a INSERM U981 , Villejuif , France.|b Université Paris-Sud , Kremlin-Bicêtre , France.
authors.forename: Melissa
authors.initials: M
authors.lastname: Leriche
authors.affiliation: a INSERM U981 , Villejuif , France.|b Université Paris-Sud , Kremlin-Bicêtre , France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Welsch
authors.affiliation: a INSERM U981 , Villejuif , France.|b Université Paris-Sud , Kremlin-Bicêtre , France.
authors.forename: Nyam
authors.initials: N
authors.lastname: Kamsu-Kom
authors.affiliation: c CNRS-Strasbourg University, UMR7200 , Illkirch , France.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: c CNRS-Strasbourg University, UMR7200 , Illkirch , France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Desaubry
authors.affiliation: a INSERM U981 , Villejuif , France.|d Institut Curie, PSL Research University, CNRS UMR3348 , Orsay , France.|e Université Paris Sud, Université Paris-Saclay, CNRS UMR3348 , Orsay , France.|f Equipe Labellisée Ligue Contre le Cancer , Orsay , France.
authors.forename: Stéphan
authors.initials: S
authors.lastname: Vagner
authors.affiliation: a INSERM U981 , Villejuif , France.|b Université Paris-Sud , Kremlin-Bicêtre , France.|g Gustave Roussy, Dermato-Oncology , Villejuif , France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Robert
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D039601:Eukaryotic Initiation Factor-4A / Q000378:metabolism*; D039562:Eukaryotic Initiation Factor-4F / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000473:pathology*; D008565:Membrane Proteins / Q000235:genetics*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*
chemical_list: D039562:Eukaryotic Initiation Factor-4F; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D020929:Mitogen-Activated Protein Kinase Kinases; D039601:Eukaryotic Initiation Factor-4A; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human
keywords: MEK; NRAS; eIF4A inhibitors; eIF4F; mRNA translation