# Site-directed RNA Editing to Modulate Kinase Activity as a Chemotherapeutic

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2021 · $38,201

## Abstract

PROJECT SUMMARY
 The development of small molecules that target dysregulated protein kinases led to a paradigm shift in
the treatment of cancer. However, the need for novel methods of kinase inhibition is demonstrated by selectivity
challenges and the emergence of drug resistance. This proposal explores how RNA editing by Adenosine
Deaminase Acting on RNA (ADAR) enzymes can be used to modulate target protein activity in cancers, through
the optimization of guide oligonucleotides that promote editing in specific sequence contexts. The ADAR family
of enzymes converts adenosine to inosine in RNA, and can be directed to a target adenosine by a
complementary guide oligonucleotide. Thus far, the field of RNA editing by ADAR enzymes has focused on
correcting disease-causative premature termination codons, due to ADAR’s preference for editing adenosines
within a termination codon. However, lysine codons are known to be deaminated by ADARs, and are of particular
interest due to the presence of a conserved catalytic lysine residue in protein kinases. Reaction of the lysine
codon with ADAR2 would produce an arginine codon: a known inactivating mutation in protein kinases. To drive
editing at the catalytic lysine within kinase mRNA, an established rational design approach to guide
oligonucleotide chemical modifications will be used. Our strategy for site-directed RNA editing has high
therapeutic potential because it utilizes endogenous ADAR enzymes, and therefore only requires the delivery of
a guide oligonucleotide. While enzyme delivery faces barriers in efficiency and immune stimulation,
oligonucleotide therapies have had recent successes in targeted delivery. The central hypothesis of this project
is that guide oligonucleotide-directed editing of protein kinase mRNA will lead to a reduction in downstream cell
signaling in cancers. Aim 1 will define how guide RNA modifications affect editing of target adenosines in lysine
codons via oligonucleotide chemical synthesis, and in vitro activity assays. Aim 2 will evaluate the effect of protein
kinase mRNA editing on protein phosphorylation and apoptosis in glioblastoma cells. Training in cell culture,
Western blotting, and fluorescence microscopy will enable the cellular analysis of protein kinase mRNA editing.
This proof of principle experiment will have broad implications in cancer therapeutics by establishing the efficacy
of RNA editing to modulate disordered protein activity. More broadly this will expand the potential therapeutic
applications of ADAR editing by defining how guide RNAs can be engineered to act in non-preferred sequence
contexts.

## Key facts

- **NIH application ID:** 10313239
- **Project number:** 1F31CA265135-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Erin E Doherty
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $38,201
- **Award type:** 1
- **Project period:** 2021-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10313239

## Citation

> US National Institutes of Health, RePORTER application 10313239, Site-directed RNA Editing to Modulate Kinase Activity as a Chemotherapeutic (1F31CA265135-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10313239. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*