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Activation of endogenous retroviruses and induction of viral mimicry by MEK1/2 inhibition in pancreatic cancer

ABSTRACT: Activation of endogenous retroviruses and induction of viral mimicry by MEK1/2 inhibition in pancreatic cancer

PROVIDER: PRJNA998356 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25419823.fastq.gz	Fastqsanger.gz
	SRR25419824.fastq.gz	Fastqsanger.gz
	SRR25419825.fastq.gz	Fastqsanger.gz
	SRR25420325_1.fastq.gz	Fastqsanger.gz
	SRR25420325_2.fastq.gz	Fastqsanger.gz

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Activation of endogenous retroviruses and induction of viral mimicry by MEK1/2 inhibition in pancreatic cancer [RNA-seq]

Project description: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.

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Activation of endogenous retroviruses and induction of viral mimicry by MEK1/2 inhibition in pancreatic cancer.

Project description: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.

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Activation of endogenous retroviruses and induction of viral mimicry by MEK1/2 inhibition in pancreatic cancer

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