BioProject

While pancreatic ductal adenocarcinomas (PDAC) are addicted to KRAS-activating mutations, inhibitors of downstream effectors in the KRAS pathway, such as the clinically approved MEK1/2 kinases inhibitor Trametinib, are devoid of significant therapeutic effects. More...

While pancreatic ductal adenocarcinomas (PDAC) are addicted to KRAS-activating mutations, inhibitors of downstream effectors in the KRAS pathway, such as the clinically approved MEK1/2 kinases inhibitor Trametinib, are devoid of significant therapeutic effects. Nevertheless, the extensive rewiring of regulatory circuits driven by the attenuation of the KRAS pathway can induce novel functional states and vulnerabilities of potential therapeutic relevance. An in-depth molecular analysis of the transcriptional and epigenomic alterations occurring in PDAC cells in the initial hours after MEK1/2 inhibition by Trametinib, unveiled a massive induction of a large number of retroelements, in particular endogenous retroviruses (ERVs), that in these cells escaped epigenetic silencing. In turn, the increased abundance of ERV-derived double stranded RNAs induced a strong Interferon (IFN) response. Pathway deconvolution allowed us to track ERV activation to the early induction of the transcription factor ELF3, which extensively bound and activated non-silenced retroelements and synergized with IRF1 (Interferon regulatory factor 1) in the activation of interferons and IFN-stimulated genes. Trametinib-induced viral mimicry in PDAC may be exploited in the design of combination therapies in immuno-oncology. Overall design: To explore the transcriptional impact of Trametinib in PDAC, we generated RNA-seq data sets in two low-grade (CAPAN2 and CFPAC1) and two high-grade (MiaPaca2 and PANC1) PDAC cell lines that were sampled in the untreated condition (UT) and at multiple time points (3h, 12h and 24h) after Trametinib treatment. To investigate the role of ELF3 induction by Trametinib in the transcriptional activation of retroelements and in the activation of the IFN response, we generated RNA-seq data set of ELF3-Knockout and Wild-Type CFPAC1 cells in both untreated and treated condition (24h) after Trametinib treatment. Less...