ADAR1 deletion induced cell lethality in a subset of cancer cell lines with elevated interferon-stimulated genes, an effect partially mediated by activation of the double-stranded RNA sensor PKR.
ADAR1 is identified as a potential therapeutic target in a subset of cancers with elevated interferon-stimulated genes due to its role in preventing PKR-mediated cell lethality.
p-value: p=<0.0001
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.
Gannon et al. (Mon,) conducted a other in Cancer. ADAR1 deletion vs. Control (GFP deletion) was evaluated on Cell viability (p=<0.0001). ADAR1 deletion induced cell lethality in a subset of cancer cell lines with elevated interferon-stimulated genes, an effect partially mediated by activation of the double-stranded RNA sensor PKR.