title: eIF4F is a nexus of resistance to anti-BRAF and anti-MEK cancer therapies.
abstract: In BRAF(V600)-mutant tumours, most mechanisms of resistance to drugs that target the BRAF and/or MEK kinases rely on reactivation of the RAS-RAF-MEK-ERK mitogen-activated protein kinase (MAPK) signal transduction pathway, on activation of the alternative, PI(3)K-AKT-mTOR, pathway (which is ERK independent) or on modulation of the caspase-dependent apoptotic cascade. All three pathways converge to regulate the formation of the eIF4F eukaryotic translation initiation complex, which binds to the 7-methylguanylate cap (m(7)G) at the 5' end of messenger RNA, thereby modulating the translation of specific mRNAs. Here we show that the persistent formation of the eIF4F complex, comprising the eIF4E cap-binding protein, the eIF4G scaffolding protein and the eIF4A RNA helicase, is associated with resistance to anti-BRAF, anti-MEK and anti-BRAF plus anti-MEK drug combinations in BRAF(V600)-mutant melanoma, colon and thyroid cancer cell lines. Resistance to treatment and maintenance of eIF4F complex formation is associated with one of three mechanisms: reactivation of MAPK signalling, persistent ERK-independent phosphorylation of the inhibitory eIF4E-binding protein 4EBP1 or increased pro-apoptotic BCL-2-modifying factor (BMF)-dependent degradation of eIF4G. The development of an in situ method to detect the eIF4E-eIF4G interactions shows that eIF4F complex formation is decreased in tumours that respond to anti-BRAF therapy and increased in resistant metastases compared to tumours before treatment. Strikingly, inhibiting the eIF4F complex, either by blocking the eIF4E-eIF4G interaction or by targeting eIF4A, synergizes with inhibiting BRAF(V600) to kill the cancer cells. eIF4F not only appears to be an indicator of both innate and acquired resistance but also is a promising therapeutic target. Combinations of drugs targeting BRAF (and/or MEK) and eIF4F may overcome most of the resistance mechanisms arising in BRAF(V600)-mutant cancers.
authors: 1] Inserm UMR981, Villejuif F-94805, France [2] Université Paris-Sud XI, Kremlin-Bicêtre F-94276, France [3] Gustave Roussy, Dermato-Oncology, Villejuif F-94805, France [4].
authors: Lise
authors: L
authors: Boussemart
authors: 1] Inserm UMR981, Villejuif F-94805, France [2] Université Paris-Sud XI, Kremlin-Bicêtre F-94276, France [3].
authors: Hélène
authors: H
authors: Malka-Mahieu
authors: 1] Inserm UMR981, Villejuif F-94805, France [2].
authors: Isabelle
authors: I
authors: Girault
authors: Inserm UMR981, Villejuif F-94805, France.
authors: Delphine
authors: D
authors: Allard
authors: 1] Inserm UMR981, Villejuif F-94805, France [2] Department of Surgical and Perioperative Sciences, Umeå University, Umeå SE-90187, Sweden (O.H.); CNRS UMR3348, Institut Curie, Orsay F-91405, France (S.V.).
authors: Oskar
authors: O
authors: Hemmingsson
authors: Gustave Roussy, Pathology Department, Villejuif F-94805, France.
authors: Gorana
authors: G
authors: Tomasic
authors: Gustave Roussy, Dermato-Oncology, Villejuif F-94805, France.
authors: Marina
authors: M
authors: Thomas
authors: CNRS-Strasbourg University, UMR7200, Illkirch F-67400, France.
authors: Christine
authors: C
authors: Basmadjian
authors: CNRS-Strasbourg University, UMR7200, Illkirch F-67400, France.
authors: Nigel
authors: N
authors: Ribeiro
authors: CNRS-Strasbourg University, UMR7200, Illkirch F-67400, France.
authors: Frédéric
authors: F
authors: Thuaud
authors: Gustave Roussy, Dermato-Oncology, Villejuif F-94805, France.
authors: Christina
authors: C
authors: Mateus
authors: Gustave Roussy, Dermato-Oncology, Villejuif F-94805, France.
authors: Emilie
authors: E
authors: Routier
authors: Inserm UMR981, Villejuif F-94805, France.
authors: Nyam
authors: N
authors: Kamsu-Kom
authors: Inserm UMR981, Villejuif F-94805, France.
authors: Sandrine
authors: S
authors: Agoussi
authors: 1] Université Paris-Sud XI, Kremlin-Bicêtre F-94276, France [2] Gustave Roussy, Dermato-Oncology, Villejuif F-94805, France.
authors: Alexander M
authors: AM
authors: Eggermont
authors: CNRS-Strasbourg University, UMR7200, Illkirch F-67400, France.
authors: Laurent
authors: L
authors: Désaubry
authors: 1] Inserm UMR981, Villejuif F-94805, France [2] Université Paris-Sud XI, Kremlin-Bicêtre F-94276, France [3] Gustave Roussy, Dermato-Oncology, Villejuif F-94805, France.
authors: Caroline
authors: C
authors: Robert
authors: 1] Inserm UMR981, Villejuif F-94805, France [2] Université Paris-Sud XI, Kremlin-Bicêtre F-94276, France [3] Gustave Roussy, Dermato-Oncology, Villejuif F-94805, France [4] Department of Surgical and Perioperative Sciences, Umeå University, Umeå SE-90187, Sweden (O.H.); CNRS UMR3348, Institut Curie, Orsay F-91405, France (S.V.).
authors: Stéphan
authors: S
authors: Vagner
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D039601:Eukaryotic Initiation Factor-4A / Q000037:antagonists & inhibitors / Q000378:metabolism; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D039562:Eukaryotic Initiation Factor-4F / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D039603:Eukaryotic Initiation Factor-4G / Q000378:metabolism; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D013964:Thyroid Neoplasms / Q000473:pathology; D014315:Triterpenes / Q000494:pharmacology; D000077484:Vemurafenib; D023041:Xenograft Model Antitumor Assays; D001572:Benzofurans
chemical_list: D000970:Antineoplastic Agents; D039601:Eukaryotic Initiation Factor-4A; D039561:Eukaryotic Initiation Factor-4E; D039562:Eukaryotic Initiation Factor-4F; D039603:Eukaryotic Initiation Factor-4G; D007211:Indoles; D020929:Mitogen-Activated Protein Kinase Kinases; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D013449:Sulfonamides; D014315:Triterpenes; D000077484:Vemurafenib; C489897:silvestrol; D001572:Benzofurans; C482119:BRAF protein, human