Identification of ADAR1 adenosine deaminase dependency in a subset of cancer cells

Hugh S. Gannon, Tao Zou, Michael K. Kiessling, Galen F. Gao, Diana Cai, Peter S. Choi, Alexandru P. Ivan, Ilana Buchumenski, Ashton C. Berger, Jonathan T. Goldstein, Andrew D. Cherniack, Francisca Vazquez, Aviad Tsherniak, Erez Y. Levanon, William C. Hahn and Matthew Meyerson ()
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Hugh S. Gannon: Dana-Farber Cancer Institute
Tao Zou: Dana-Farber Cancer Institute
Michael K. Kiessling: University of Zurich and University Hospital Zürich
Galen F. Gao: Broad Institute of Harvard and MIT
Diana Cai: Dana-Farber Cancer Institute
Peter S. Choi: Dana-Farber Cancer Institute
Alexandru P. Ivan: Dana-Farber Cancer Institute
Ilana Buchumenski: Bar-Ilan University
Ashton C. Berger: Broad Institute of Harvard and MIT
Jonathan T. Goldstein: Broad Institute of Harvard and MIT
Andrew D. Cherniack: Dana-Farber Cancer Institute
Francisca Vazquez: Broad Institute of Harvard and MIT
Aviad Tsherniak: Broad Institute of Harvard and MIT
Erez Y. Levanon: Bar-Ilan University
William C. Hahn: Dana-Farber Cancer Institute
Matthew Meyerson: Dana-Farber Cancer Institute

Nature Communications, 2018, vol. 9, issue 1, 1-10

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.

Date: 2018
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DOI: 10.1038/s41467-018-07824-4

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