Evaluating the therapeutic potential of ADAR1 inhibition for triple-negative breast cancer

Kung, Che Pei; Cottrell, Kyle A.; Ryu, Sua; Bramel, Emily R.; Kladney, Raleigh D.; Bao, Emily A.; Freeman, Eric C.; Sabloak, Thwisha; Maggi, Leonard B.; Weber, Jason D.

doi:10.1038/s41388-020-01515-5

Cited by 56 publications

(86 citation statements)

References 53 publications

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Section: Introductionmentioning

confidence: 69%

“…Consistent with its proposed role in preventing dsRNA sensing, loss of ADAR in many human cancer cell lines leads to activation of the type I IFN pathway through activation of MAVS and translation repression by activation of PKR (11)(12)(13). The growth phenotype of ADAR depletion can be rescued by disruption of type I IFN signaling or knockdown of PKR (11)(12)(13). Because of the importance of ADAR expression in many human cancer cell lines, several groups have proposed the use of ADAR inhibitors as a therapy for lung, breast and thyroid cancers (11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 71%

“…Several recent studies have highlighted the importance of ADAR expression in a wide range of cancer cell lines (11)(12)(13)(14). In ADAR-dependent cells, loss of ADAR causes activation of PKR and the type I IFN pathway leading to reduced proliferation and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…Loss of ADAR in ADAR-dependent cells has been shown to cause activation of the dsRNA sensor PKR (11)(12)(13). It has been proposed that loss of A-to-I editing by ADAR leads to accumulation of dsRNA leading to activation and autophosphorylation of PKR (9).…”

Section: Treatment With 8-chloroadenosine or 8-azaadenosine Does Not Activate Pkrmentioning

confidence: 99%

“…Depletion of ADAR in numerous cancer cell lines causes reduced proliferation and increased apoptosis (11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

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8-azaadenosine and 8-chloroadenosine are not selective inhibitors of ADAR

Cottrell

Torres

Weber

2021

Preprint

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The RNA editing enzyme ADAR, is an attractive therapeutic target for multiple cancers. Through its deaminase activity, ADAR edits adenosine to inosine in dsRNAs. Loss of ADAR in some cancer cell lines causes activation of the type I interferon pathway and the PKR translational repressor, leading to inhibition of proliferation and stimulation of cell death. As such, inhibition of ADAR function is a viable therapeutic strategy for many cancers. However, there are no FDA approved inhibitors of ADAR. Two small molecules have been previously described as inhibitors of ADAR: 8-azaadenosine and 8-chloroadenosine. Here we show that neither molecule is a selective inhibitor of ADAR. Both 8-azaadenosine and 8-chloroadenosine show similar toxicity to ADAR-dependent and independent cancer cell lines. Furthermore, the toxicity of both small molecules is comparable between cell lines with knockdown of ADAR and cells with unperturbed ADAR expression. Treatment with neither molecule causes activation of PKR. Finally, treatment with either molecule has no effect on A-to-I editing of an ADAR substrate. Together these data show that 8-azaadenosine and 8-chloroadenosine are not suitable small molecules for therapies that require selective inhibition of ADAR, and neither should be used in preclinical studies as ADAR inhibitors.

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Section: Introductionmentioning

confidence: 69%

Section: Introductionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Treatment With 8-chloroadenosine or 8-azaadenosine Does Not Activate Pkrmentioning

confidence: 99%

“…Depletion of ADAR in numerous cancer cell lines causes reduced proliferation and increased apoptosis (11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

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8-azaadenosine and 8-chloroadenosine are not selective inhibitors of ADAR

Cottrell

Torres

Weber

2021

Preprint

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Drugging the Epitranscriptome

Eggert,

Kleiner

2024

RNA as a Drug Target

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A‐to‐I RNA editing by ADAR and its therapeutic applications: From viral infections to cancer immunotherapy

Datta,

Adamska,

Bhate

et al. 2023

WIREs RNA

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ADAR deaminases catalyze adenosine‐to‐inosine (A‐to‐I) editing on double‐stranded RNA (dsRNA) substrates that regulate an umbrella of biological processes. One of the two catalytically active ADAR enzymes, ADAR1, plays a major role in innate immune responses by suppression of RNA sensing pathways which are orchestrated through the ADAR1‐dsRNA‐MDA5 axis. Unedited immunogenic dsRNA substrates are potent ligands for the cellular sensor MDA5. Upon activation, MDA5 leads to the induction of interferons and expression of hundreds of interferon‐stimulated genes with potent antiviral activity. In this way, ADAR1 acts as a gatekeeper of the RNA sensing pathway by striking a fine balance between innate antiviral responses and prevention of autoimmunity. Reduced editing of immunogenic dsRNA by ADAR1 is strongly linked to the development of common autoimmune and inflammatory diseases. In viral infections, ADAR1 exhibits both antiviral and proviral effects. This is modulated by both editing‐dependent and editing‐independent functions, such as PKR antagonism. Several A‐to‐I RNA editing events have been identified in viruses, including in the insidious viral pathogen, SARS‐CoV‐2 which regulates viral fitness and infectivity, and could play a role in shaping viral evolution. Furthermore, ADAR1 is an attractive target for immuno‐oncology therapy. Overexpression of ADAR1 and increased dsRNA editing have been observed in several human cancers. Silencing ADAR1, especially in cancers that are refractory to immune checkpoint inhibitors, is a promising therapeutic strategy for cancer immunotherapy in conjunction with epigenetic therapy. The mechanistic understanding of dsRNA editing by ADAR1 and dsRNA sensing by MDA5 and PKR holds great potential for therapeutic applications.This article is categorized under: RNA Processing > RNA Editing and Modification RNA in Disease and Development > RNA in Disease

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Evaluating the therapeutic potential of ADAR1 inhibition for triple-negative breast cancer

Cited by 56 publications

References 53 publications

8-azaadenosine and 8-chloroadenosine are not selective inhibitors of ADAR

8-azaadenosine and 8-chloroadenosine are not selective inhibitors of ADAR

Drugging the Epitranscriptome

A‐to‐I RNA editing by ADAR and its therapeutic applications: From viral infections to cancer immunotherapy

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