ADAR1 masks the cancer immunotherapeutic promise of ZBP1-driven necroptosis

Ting Zhang, Chaoran Yin, Aleksandr Fedorov, Liangjun Qiao, Hongliang Bao, Nazar Beknazarov, Shiyu Wang, Avishekh Gautam, Riley M. Williams, Jeremy Chase Crawford, Suraj Peri, Vasily Studitsky, Amer A. Beg, Paul G. Thomas, Carl Walkley, Yan Xu, Maria Poptsova, Alan Herbert () and Siddharth Balachandran ()
Additional contact information
Ting Zhang: Fox Chase Cancer Center
Chaoran Yin: Fox Chase Cancer Center
Aleksandr Fedorov: National Research University Higher School of Economics
Liangjun Qiao: Chongqing Medical University
Hongliang Bao: University of Miyazaki
Nazar Beknazarov: National Research University Higher School of Economics
Shiyu Wang: University of Miyazaki
Avishekh Gautam: Fox Chase Cancer Center
Riley M. Williams: Fox Chase Cancer Center
Jeremy Chase Crawford: St Jude Children’s Research Hospital
Suraj Peri: Fox Chase Cancer Center
Vasily Studitsky: Fox Chase Cancer Center
Amer A. Beg: Moffitt Cancer Center and Research Institute
Paul G. Thomas: St Jude Children’s Research Hospital
Carl Walkley: University of Melbourne
Yan Xu: University of Miyazaki
Maria Poptsova: National Research University Higher School of Economics
Alan Herbert: National Research University Higher School of Economics
Siddharth Balachandran: Fox Chase Cancer Center

Nature, 2022, vol. 606, issue 7914, 594-602

Abstract: Abstract Only a small proportion of patients with cancer show lasting responses to immune checkpoint blockade (ICB)-based monotherapies. The RNA-editing enzyme ADAR1 is an emerging determinant of resistance to ICB therapy and prevents ICB responsiveness by repressing immunogenic double-stranded RNAs (dsRNAs), such as those arising from the dysregulated expression of endogenous retroviral elements (EREs)1–4. These dsRNAs trigger an interferon-dependent antitumour response by activating A-form dsRNA (A-RNA)-sensing proteins such as MDA-5 and PKR5. Here we show that ADAR1 also prevents the accrual of endogenous Z-form dsRNA elements (Z-RNAs), which were enriched in the 3′ untranslated regions of interferon-stimulated mRNAs. Depletion or mutation of ADAR1 resulted in Z-RNA accumulation and activation of the Z-RNA sensor ZBP1, which culminated in RIPK3-mediated necroptosis. As no clinically viable ADAR1 inhibitors currently exist, we searched for a compound that can override the requirement for ADAR1 inhibition and directly activate ZBP1. We identified a small molecule, the curaxin CBL0137, which potently activates ZBP1 by triggering Z-DNA formation in cells. CBL0137 induced ZBP1-dependent necroptosis in cancer-associated fibroblasts and reversed ICB unresponsiveness in mouse models of melanoma. Collectively, these results demonstrate that ADAR1 represses endogenous Z-RNAs and identifies ZBP1-mediated necroptosis as a new determinant of tumour immunogenicity masked by ADAR1. Therapeutic activation of ZBP1-induced necroptosis provides a readily translatable avenue for rekindling the immune responsiveness of ICB-resistant human cancers.

Date: 2022
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DOI: 10.1038/s41586-022-04753-7

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