Abstract IA29: Role of eIF4F in anticancer drug resistance

Abstract

Abstract Recent work, including large-scale genetic and molecular analyses, identified RNA-binding proteins (RBPs) as major players in the hallmarks of cancer. Specific RBPs allow the selective regulation of cancer genes at multiple post-transcriptional levels from pre-mRNA splicing/polyadenylation to mRNA stability/translation. These multiple activities are mediated by RBP binding to mRNAs. In recent years, we have studied how the eIF4F translation initiation factor bound to the 7-methylguanosine cap structure present at the 5'-end of all cellular mRNAs contributes to tumorigenesis with a focus on its role in chemoresistance as well as the promising use of new small molecule inhibitors of the complex, including flavaglines/rocaglates, hippuristanol and pateamine A. We have specifically shown that, due to its location downstream of the the PI(3)K/AKT/mTOR pathway and the RAS-RAF-MEK-ERK-MNK mitogen-activated protein kinase (MAPK) signal transduction pathways, eIF4F is a nexus of resistance to anti-BRAF and anti-MEK therapies in both BRAF-mutated (melanoma, colon, thyroid) and NRAS-mutated (melanoma) cancer cells. Furthermore, inhibiting the eIF4A component of the eIF4F complex, with a novel flavagline (FL3) that is insensitive to P-glycoprotein-mediated multidrug resistance, synergizes with inhibiting BRAF and MEK to kill BRAF-mutant cancer cells and synergizes with inhibiting MEK to kill NRAS-mutant cancer cells in melanoma. In parallel, while investigating a set of data based on high-throughput sequencing of polyadenylated transcripts 3'-ends (3'-Seq), we have found that a short eIF4E mRNA isoform is generated through alternative use on an intronic polyadenylation (IPA) site. The global generation of transcripts with shorter 3' untranslated region (3'UTR) is known to occur during enhanced cell proliferation and transformation into cancer cells. However, the involvement of alternative polyadenylation in the response to targeted therapies and in the spreading of cancer cells to metastatic sites is unknown. IPA site usage is known to be widely inhibited by the U1 small ribonucleoprotein particle (U1) bound to an adjacent 5' splice site (5'ss). We have found that targeting U1 with an antisense oligonucleotide (U1-ASO) leads to activation of the use of IPA sites in the eIF4E gene but also in several genes with functions enriched in cell movement and involved in the RAS-RAF-MEK-ERK mitogen-activated protein kinase (MAPK) and PI(3)K-AKT-mTOR signal transduction pathways. We have also demonstrated that the specificity of IPA regulation by U1 during tumor cell spreading is provided by the regulation of its binding to specific 5'ss by the RBP and U1-interacting splicing factor TIA1. The significance of these findings in tumor cell spreading and in the response to targeted therapies will be discussed. Citation Format: Galina Boldina, Maricarmen Vallejos, Delphine Allard, Isabelle Girault, Hélène Malka-Mahieu, Laurent Désaubry, Martin Dutertre, Caroline Robert, Stéphan Vagner. Role of eIF4F in anticancer drug resistance. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr IA29.