Alice Cortesi, Francesco Gandolfi, Fabiana Arco, Pierluigi Di Chiaro, Emanuele Valli, Sara Polletti, Roberta Noberini, Francesco Gualdrini, Sergio Attanasio, Francesca Citron, I-Lin Ho, Rutvi Shah, Er-Yen Yen, Mara Cetty Spinella, Simona Ronzoni, Simona Rodighiero, Nico Mitro, Tiziana Bonaldi, Serena Ghisletti, Silvia Monticelli, Andrea Viale, Giuseppe Riccardo Diaferia, Gioacchino Natoli
While pancreatic ductal adenocarcinomas (PDACs) are addicted to KRAS-activating mutations, inhibitors of downstream KRAS effectors, such as the MEK1/2 kinase inhibitor trametinib, are devoid of therapeutic effects. However, the extensive rewiring of regulatory circuits driven by the attenuation of the KRAS pathway may induce vulnerabilities of 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 the induction of endogenous retroviruses (ERVs) escaping epigenetic silencing, leading to the production of double-stranded RNAs and the increased expression of interferon (IFN) genes...
March 29, 2024: Science Advances