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.

STAT1 Promotes KRAS Colon Tumor Growth and Susceptibility to Pharmacological Inhibition of Translation Initiation Factor eIF4A

“…Consistent with this hypothesis, we observed that PDCD4-deficient HCT116 cells by shRNA expression were more susceptible than PDCD4-proficient cells to death after treatment with the flavagline FL3 (Fig. 3), which is a specific and potent eIF4A inhibitor (19,28). We also found that treatment with FL3 substantially increased the susceptibility of STAT1-proficient HCT116 cells to death compared with STAT1-deficient HCT116 cells (Fig.…”

“…The PDCD4 shRNA was expressed from psiRNA-hH1hygro G2 vector (18). Human IFNa and IFNg was obtained from Biosource (Invitrogen), whereas treatment with FL3 was performed as described previously (19).…”

“…Mice were treated with 15 mg/kg body weight of FL3 delivered by intraperitoneal injections every day for 2 weeks based on the established protocol (19). The animal studies were performed in accordance with approved protocols and regulations by the Animal Welfare Committee of McGill University (Montreal, Quebec, Canada; protocol #5754).…”

CTCF prevents genomic instability by promoting homologous recombination-directed DNA double-strand break repair

“…S7A), and confirmed by a proximity ligation assay (PLA) (37), which allows direct visualization of in vivo protein-protein interactions (Fig. 6L).…”

eIF4A1 is a promising new therapeutic target in ER-negative breast cancer

“…Inhibition of eIF4A function with hippuristanol synergized with anti-BRAF or anti-MEK inhibitors and the data suggested that combinations of drugs targeting BRAF and eIF4A (as part of eIF4F) would be sufficient to overcome most resistance mechanisms in BRAF (V600)-mutant cancers and provide new treatment options for patients with this aggressive cancer. 12 However, despite these studies, the frequency and role of increased eIF4A1 activity in tumorigenesis has not been extensively investigated. Modelska et al carried out an important large-scale study to determine the clinical significance of expression of eIF4A1 and its modulators in breast cancer by scoring tissue microarrays derived from~4000 patients.…”