Publication Date:
2014-08-01
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Boussemart, Lise -- Malka-Mahieu, Helene -- Girault, Isabelle -- Allard, Delphine -- Hemmingsson, Oskar -- Tomasic, Gorana -- Thomas, Marina -- Basmadjian, Christine -- Ribeiro, Nigel -- Thuaud, Frederic -- Mateus, Christina -- Routier, Emilie -- Kamsu-Kom, Nyam -- Agoussi, Sandrine -- Eggermont, Alexander M -- Desaubry, Laurent -- Robert, Caroline -- Vagner, Stephan -- England -- Nature. 2014 Sep 4;513(7516):105-9. doi: 10.1038/nature13572. Epub 2014 Jul 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Inserm UMR981, Villejuif F-94805, France [2] Universite Paris-Sud XI, Kremlin-Bicetre F-94276, France [3] Gustave Roussy, Dermato-Oncology, Villejuif F-94805, France [4]. ; 1] Inserm UMR981, Villejuif F-94805, France [2] Universite Paris-Sud XI, Kremlin-Bicetre F-94276, France [3]. ; 1] Inserm UMR981, Villejuif F-94805, France [2]. ; Inserm UMR981, Villejuif F-94805, France. ; 1] Inserm UMR981, Villejuif F-94805, France [2] Department of Surgical and Perioperative Sciences, Umea University, Umea SE-90187, Sweden (O.H.); CNRS UMR3348, Institut Curie, Orsay F-91405, France (S.V.). ; Gustave Roussy, Pathology Department, Villejuif F-94805, France. ; Gustave Roussy, Dermato-Oncology, Villejuif F-94805, France. ; CNRS-Strasbourg University, UMR7200, Illkirch F-67400, France. ; 1] Universite Paris-Sud XI, Kremlin-Bicetre F-94276, France [2] Gustave Roussy, Dermato-Oncology, Villejuif F-94805, France. ; 1] Inserm UMR981, Villejuif F-94805, France [2] Universite Paris-Sud XI, Kremlin-Bicetre F-94276, France [3] Gustave Roussy, Dermato-Oncology, Villejuif F-94805, France. ; 1] Inserm UMR981, Villejuif F-94805, France [2] Universite Paris-Sud XI, Kremlin-Bicetre F-94276, France [3] Gustave Roussy, Dermato-Oncology, Villejuif F-94805, France [4] Department of Surgical and Perioperative Sciences, Umea University, Umea SE-90187, Sweden (O.H.); CNRS UMR3348, Institut Curie, Orsay F-91405, France (S.V.).〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25079330" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Antineoplastic Agents/pharmacology
;
Cell Death/drug effects
;
Cell Line, Tumor
;
Colonic Neoplasms/pathology
;
*Drug Resistance, Neoplasm/drug effects
;
Drug Synergism
;
Eukaryotic Initiation Factor-4A/antagonists & inhibitors/metabolism
;
Eukaryotic Initiation Factor-4E/metabolism
;
Eukaryotic Initiation Factor-4F/*antagonists & inhibitors/chemistry/*metabolism
;
Eukaryotic Initiation Factor-4G/metabolism
;
Female
;
Humans
;
Indoles/pharmacology
;
MAP Kinase Signaling System/drug effects
;
Melanoma/*drug therapy/genetics/pathology
;
Mice
;
Mitogen-Activated Protein Kinase Kinases/*antagonists & inhibitors
;
Phosphorylation/drug effects
;
Protein Binding/drug effects
;
Protein Kinase Inhibitors/pharmacology
;
Proto-Oncogene Proteins B-raf/*antagonists & inhibitors/genetics
;
Signal Transduction/drug effects
;
Sulfonamides/pharmacology
;
Thyroid Neoplasms/pathology
;
Triterpenes/pharmacology
;
Xenograft Model Antitumor Assays
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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