Abstract A23: eIF4F is a key and targetable convergence nexus of multiple mechanisms of resistance to anti-BRAF and anti-MEK cancer therapies

Abstract

Abstract The V600E mutation in BRAF is the most frequent oncogenic mutation in human cancers, and can be targeted by specific anti-BRAF agents. However, several mechanisms of resistance have been identified, leading 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). These pathways converge to regulate the formation of the eIF4F translation initiation complex that binds to the 7-methylguanosine cap at the 5′ end of mRNAs, thereby modulating mRNA translation of specific mRNAs. We addressed the potential role of the eIF4F eukaryotic translation initiation complex in resistance or sensitivity to anti-BRAF and anti-MEK agents in several BRAF mutant cells, xenografts and tumors. Our data demonstrate that the formation of the eIF4F complex is associated with most resistance mechanisms to these targeted therapies, independently of their capacity to reactivate or not the MAP-kinase pathway. Formation of this complex can be explored in tumor samples using a new in situ technology. Inhibitors of the eIF4F complex synergize with anti-BRAF agents and can thus reverse resistance. Citation Format: Lise Boussemart, Helene Malka-Mahieu, Isabelle Girault, Delphine Allard, Oskar Hemmingson, Nyam Kamsu-Kom, Sandrine Agoussi, Alexander Eggermont, Laurent Desaubry, Caroline Robert, Stephan Vagner. eIF4F is a key and targetable convergence nexus of multiple mechanisms of resistance to anti-BRAF and anti-MEK cancer therapies. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr A23.