Faculty, Staff and Student Publications

Publication Date

3-29-2024

Journal

Science Advances

Abstract

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. We tracked ERV activation to the early induction of the transcription factor ELF3, which extensively bound and activated nonsilenced retroelements and synergized with IRF1 (interferon regulatory factor 1) in the activation of IFNs and IFN-stimulated genes. Trametinib-induced viral mimicry in PDAC may be exploited in the rational design of combination therapies in immuno-oncology.

Keywords

Humans, Endogenous Retroviruses, Signal Transduction, Proto-Oncogene Proteins p21(ras), Pancreatic Neoplasms, Carcinoma, Pancreatic Ductal

Comments

Associated Data

PMID: 38536927

DOI

10.1126/sciadv.adk5386

PMID

38536927

PMCID

PMC10971493

PubMedCentral® Posted Date

March 2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

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