Identification of ADAR1i-124: The first effective A-to-I RNA editing inhibitor with promising cancer therapeutic potential

TL;DR

Researchers discovered ADAR1i-124, a new drug that blocks RNA editing and shows potential for treating cancer by triggering cell death pathways.

Contribution

The discovery of ADAR1i-124, the first effective inhibitor of A-to-I RNA editing with cancer therapeutic potential.

Findings

ADAR1i-124 inhibits both ADAR1p150 and ADAR1p110 and activates MDA5 and ZBP1 pathways.

Combining ADAR1i-124 with 5-Aza-CdR overcomes resistance in some cancer cells.

ADAR1i-124 induces apoptosis through dsRNA-MDA5 or -PKR pathways.

Abstract

Two ADAR1 isoforms, p150 and p110, are involved in adenosine-to-inosine RNA editing. ADAR1p150-mediated hyper-editing of endogenous dsRNAs prevents their activation of type I interferon signaling-mediated via Melanoma Differentiation-Associated Protein 5 (MDA5), which enables cancer resistance to immune checkpoint blockade. ADAR1p150 also inhibits Z-RNA-mediated activation of Z-DNA Binding Protein 1 (ZBP1) and induction of necroptosis. ADAR1p110 suppresses the formation of telomeric repeat R-loops, which would otherwise induce apoptosis in telomerase-reactivated cancer cells. Together, ADAR1 inhibitors could serve as novel cancer therapeutics. Here, we identified, ADAR1i-124, which inhibits the catalytic activities of both ADAR1p150 and ADAR1p110. ADAR1i-124 activated MDA5 and ZBP1 pathways and dose-dependently inhibited viability across different types of cancer cell lines. Some cancer cell lines, unresponsive to ADAR1i-124 alone, became responsive when co-treated with 5-Aza-CdR. The DNA methylase inhibitor reactivated endogenous retroviruses, leading to the formation of retrovirus dsRNAs and the emergence of a new ADAR1 dependency. Our study establishes the potential of ADAR1i-124 as a future cancer therapeutic.

•Identified ADAR1i-124 as a selective inhibitor of the ADAR1 A-to-I RNA editing activity•ADAR1i-124 activates the Z-RNA-ZBP1-necroptosis pathway in ADAR1p150High cancer cells•ADAR1i-124 activates also the dsRNA-MDA5 or -PKR pathway and induces apoptosis•Combined use of 5-Aza-CdR overcomes resistance to ADAR1i-124 in select cancer cells

Identified ADAR1i-124 as a selective inhibitor of the ADAR1 A-to-I RNA editing activity

ADAR1i-124 activates the Z-RNA-ZBP1-necroptosis pathway in ADAR1p150High cancer cells

ADAR1i-124 activates also the dsRNA-MDA5 or -PKR pathway and induces apoptosis

Combined use of 5-Aza-CdR overcomes resistance to ADAR1i-124 in select cancer cells

Therapeutics; Enzymology; Nucleic acids; Properties of biomolecules; Cancer

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