Abstract
Systematic exploration of cancer cell vulnerabilities can inform the development of novel cancer therapeutics. Here, through analysis of genome-scale loss-of-function datasets, we identify adenosine deaminase acting on RNA (ADAR or ADAR1) as an essential gene for the survival of a subset of cancer cell lines. ADAR1-dependent cell lines display increased expression of interferon-stimulated genes. Activation of type I interferon signaling in the context of ADAR1 deficiency can induce cell lethality in non-ADAR1-dependent cell lines. ADAR deletion causes activation of the double-stranded RNA sensor, protein kinase R (PKR). Disruption of PKR signaling, through inactivation of PKR or overexpression of either a wildtype or catalytically inactive mutant version of the p150 isoform of ADAR1, partially rescues cell lethality after ADAR1 loss, suggesting that both catalytic and non-enzymatic functions of ADAR1 may contribute to preventing PKR-mediated cell lethality. Together, these data nominate ADAR1 as a potential therapeutic target in a subset of cancers.
Highlights
Systematic exploration of cancer cell vulnerabilities can inform the development of novel cancer therapeutics
Since the MDA5/MAVS cytosolic RNA sensing pathway is not essential for ADAR genetic dependency, we examined whether the cGAS/STING cytosolic DNA sensing pathway may mediate the cell lethality induced by ADAR1 loss
An elevated interferon gene expression signature is predictive of ADAR1dependence, the mechanisms underlying this sensitivity to ADAR knockout will require further investigation
Summary
Systematic exploration of cancer cell vulnerabilities can inform the development of novel cancer therapeutics. Disruption of PKR signaling, through inactivation of PKR or overexpression of either a wildtype or catalytically inactive mutant version of the p150 isoform of ADAR1, partially rescues cell lethality after ADAR1 loss, suggesting that both catalytic and non-enzymatic functions of ADAR1 may contribute to preventing PKR-mediated cell lethality Together, these data nominate ADAR1 as a potential therapeutic target in a subset of cancers. Lung cancer cells may harbor specific genomic or functional alterations that render them vulnerable to particular genetic perturbations[7,8] Identification of these synthetic lethal interactions may offer an opportunity for the development of novel classes of therapies for lung cancer. Our data suggest that ADAR1 may represent a potential therapeutic target in cancers displaying activation of interferon response pathways
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