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

被引：156

作者：

Gannon, Hugh S. ^{[1
,2
]}

Zou, Tao ^{[1
,2
]}

Kiessling, Michael K. ^{[3
,4
,5
]}

Gao, Galen F. ^{[2
]}

Cai, Diana ^{[1
,2
]}

Choi, Peter S. ^{[1
,2
]}

Ivan, Alexandru P. ^{[1
]}

Buchumenski, Ilana ^{[6
]}

Berger, Ashton C. ^{[2
]}

Goldstein, Jonathan T. ^{[2
]}

Cherniack, Andrew D. ^{[1
,2
]}

Vazquez, Francisca ^{[2
]}

Tsherniak, Aviad ^{[2
]}

Levanon, Erez Y. ^{[6
]}

Hahn, William C. ^{[1
,2
,7
,8
]}

Meyerson, Matthew ^{[1
,2
,8
,9
]}

机构：

[1] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

[2] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA

[3] Univ Zurich, Dept Gastroenterol & Hepatol, CH-8091 Zurich, Switzerland

[4] Univ Hosp Zurich, CH-8091 Zurich, Switzerland

[5] Univ Zurich, Univ Hosp Zurich, Dept Med Oncol & Hematol, CH-8091 Zurich, Switzerland

[6] Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, IL-52900 Ramat Gan, Israel

[7] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA

[8] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02215 USA

[9] Harvard Med Sch, Dept Pathol, Boston, MA 02115 USA

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

关键词：

PROTEIN-KINASE PKR; SYNTHETIC LETHALITY; RNA; INTERFERON; MUTATIONS; ENZYME; INHIBITION; SUPPRESSES; ACTIVATION;

D O I：

10.1038/s41467-018-07824-4

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：10

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