Abstract CCOS14-04: Resistance to anti-BRAF and anti-MEK agents: Lost in translation
Authors: Robert Caroline 
Published: May 2015

Abstract
The V600E mutation in BRAF (v-raf murine sarcoma viral oncogene homolog B) is the most frequent oncogenic mutation in human cancers, and can be targeted by specific anti-BRAF agents (e.g. vemurafenib, dabrafenib). However, in spite of their proven efficacy, the effect of these drugs is limited by primary, or, more frequently, secondary resistance, that significantly counteracts their clinical benefit and has tempered the initial enthusiasm associated with their use in the clinic. Several resistance mechanisms have been identified. They can lead to reactivation of the initially blocked MAP-kinase pathway (known as ERK-dependent mechanisms) or reactivation of alternative ones, like the PI3K-AKT-mTOR pathway, or inhibition of the apoptotic cascade (ERK-independent).
Recent evidence shows that the regulation of mRNA translation plays a pivotal role in gene expression. Furthermore, the complex machinery that regulates mRNA translation is a key element in the interplay between the two critical signalling MAPK and PI3-kinase pathways and the apoptosis cascade. However, it is unknown whether the response to anti-cancer targeted therapies is modulated by the activity of translation factors.
By addressing the potential role of the eIF4F eukaryotic translation initiation complex, which regulates the initiation of the cap-dependent translation, in resistance or sensitivity to anti-BRAF and anti-MEK agents in several BRAF mutant cells, xenografts and tumors, it can be demonstrated that the formation of the eIF4F complex is associated with most resistance mechanisms to these targeted therapies. In several melanoma cell lines, resistance to anti-BRAF, anti-MEK or to both agents was consistently associated with persistent binding of the cap binding protein eIF4E to the eIF4G scaffolding protein, forming, together with eIF4A, the eIF4F complex. Conversely, sensitive cell lines and responding tumors from patients exhibited down-regulation of eIF4F complex formation and a concomitant increase in the binding of eIF4E to its inhibitory 4E binding protein (4EBP1). Binding of eIF4E to either eiF4G or 4EBP-1 was also visualized in situ in cell lines and in tumor samples.
By exploring the resistance processes involved in the resistant cell lines that we studied, we found that these various mechanisms, independently of their capacity to reactivate or not the MAP-kinase pathway consistently favoured eIF4F complex formation over the eIF4E-4EBP-1 complex. Finally, we tested several eiF4F inhibitors that demonstrated a synergistic effect with anti-BRAF agents on resistant cell lines and in melanoma tumor xenografts.
Finally, most mechanisms of resistance to anti-BRAF and /or anti-MEK agents are associated with persistent activation of the eiF4F cap-dependent translation initiation complex that can be explored in tumor samples using a new in situ technology. These findings potentially have important applications in the clinic since, independently of the mechanism leading to its continuous activation, inhibitors of the eiF4F complex synergize with anti-BRAF agents and can thus reverse resistance.
The impact of the demonstration of a role for eIF4F in resistance to targeted anti-BRAF therapy might translate into the identification of new biomarkers and might also open new therapeutic avenues.
Citation Format: Caroline Robert. Resistance to anti-BRAF and anti-MEK agents: Lost in translation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CCOS14-04. doi:10.1158/1538-7445.AM2014-CCOS14-04