eIF4F Is a Marker of Resistance to Anti-BRAF and Anti-MEK Therapies

All mechanisms of resistance to BRAF^V600 or MEK inhibitors converge on regulation of mRNA translation by the eukaryotic translation initiation factor eIF4F complex. Boussemart, Malka-Mahieu, Girault, and colleagues investigated the role of eIF4F complex formation in the resistance to anti-BRAF and anti-MEK compounds in BRAF^V600-mutant cancers. Analysis of a panel of BRAF^V600-mutant melanoma cell lines with varying sensitivity to BRAF and MEK inhibitors revealed that treatment of sensitive cell lines with vemurafenib increased binding of eIF4E, a component of eIF4F, to the inhibitory protein eIF4E-binding protein 1 (EIF4EBP1, also known as 4EBP1) and decreased binding of eIF4E to the eIF4G scaffolding protein, thereby disrupting eIF4F-complex formation. Importantly, disruption of eIF4F after single-agent BRAF or MEK inhibitor treatment or combined BRAF–MEK inhibition was not observed in drug-resistant BRAF^V600-mutant cell lines, including a melanoma cell line with acquired BRAF inhibitor resistance and colon and papillary thyroid cancer cell lines. Preservation of eIF4F in BRAF inhibitor–resistant cell lines was mediated by reactivation of the MAPK pathway, as well as by MAPK-independent mechanisms, including liberation of eIF4E through persistent 4EBP1 phosphorylation and decreased expression of the proapoptotic protein BCL2-modifying factor (BMF), which resulted in reduced eIF4G cleavage. Furthermore, inhibition of eIF4F via disruption of eIF4E binding to eIF4G or by targeting eIF4A suppressed the proliferation of BRAF inhibitor–resistant but not BRAF inhibitor–sensitive melanoma cell lines, and exhibited a synergistic effect when combined with BRAF inhibition, suggesting eIF4F as a potential therapeutic target for anti-BRAF and anti-MEK resistance. Moreover, assessment of tumor samples from patients with metastatic melanoma confirmed the correlation between BRAF inhibitor resistance and sustained eIF4F complex formation. These observations highlight the potential of eIF4F as a marker of anti-BRAF and anti-MEK therapy resistance and suggest that dual inhibition of BRAF/MEK and eIF4F may overcome drug resistance.

Boussemart L, Malka-Mahieu H, Girault I, Allard D, Hemmingsson O, Tomasic G, et al. eIF4F is a nexus of resistance to anti-BRAF and anti-MEK cancer therapies. Nature Jul 27 2014 [Epub ahead of print].