Identification of ADAR1 adenosine deaminase dependency in a subset of cancer cells. Issue 1 (December 2018)

• Record Type: Journal Article
• Authors: Gannon, Hugh; Zou, Tao; Kiessling, Michael; Gao, Galen; Cai, Diana; Choi, Peter; Ivan, Alexandru; Buchumenski, Ilana; Berger, Ashton; Goldstein, Jonathan; Cherniack, Andrew; Vazquez, Francisca; Tsherniak, Aviad; Levanon, Erez; Hahn, William; Meyerson, Matthew
• Is Part Of: Nature communications. Volume 9:Issue 1(2018)
• Page Start: 1
• Page End: 10
• Publication Date: 2018-12
• Subjects: Biology -- Periodicals; Physical sciences -- Periodicals; 505
• DOI: 10.1038/s41467-018-07824-4
• Languages: English
• ISSNs: 2041-1723

Abstract

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. Specific cancer cell vulnerabilities can provide an opportunity for the development of novel cancer therapeutics. In this study the authors demonstrate that targeting ADAR1 represents a potential therapeutic vulnerability in cancers with activated interferon response signatures.