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.