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Nature. 2014 Sep 4;513(7516):105-9. doi: 10.1038/nature13572. Epub 2014 Jul 27.

eIF4F is a nexus of resistance to anti-BRAF and anti-MEK cancer therapies.

Author information

1
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].
2
1] Inserm UMR981, Villejuif F-94805, France [2] Université Paris-Sud XI, Kremlin-Bicêtre F-94276, France [3].
3
1] Inserm UMR981, Villejuif F-94805, France [2].
4
Inserm UMR981, Villejuif F-94805, France.
5
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.).
6
Gustave Roussy, Pathology Department, Villejuif F-94805, France.
7
Gustave Roussy, Dermato-Oncology, Villejuif F-94805, France.
8
CNRS-Strasbourg University, UMR7200, Illkirch F-67400, France.
9
1] Université Paris-Sud XI, Kremlin-Bicêtre F-94276, France [2] Gustave Roussy, Dermato-Oncology, Villejuif F-94805, France.
10
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.
11
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.).

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.

Comment in

PMID:
25079330
DOI:
10.1038/nature13572
[Indexed for MEDLINE]

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