The phenomenon of “RNA editing” is a relatively recent discovery with exciting implications. RNA editing is a process that modifies the sequence of RNA after it is copied from the DNA (the gene). One type of RNA editing converts adenosine (A) residues to inosine (I) specifically in double-stranded RNA (dsRNA), and this process is called A-to-I RNA editing. A-to-I RNA editing is carried out by a class of enzymes called ADARs (adenosine deaminases acting on RNA). To date, three ADAR enzymes (ADAR1, ADAR2, ADAR3) have been discovered in mammals. ADAR edits many RNA messages copied from “non-coding and repetitive sequences”. We identified ADAR1, the pioneer member of the ADAR gene family, and made major contributions to the development of the A-to-I RNA editing field.

Melanoma is one of the most commonly diagnosed cancers in the United States. There were an estimated 186,680 new cases of melanoma and 7,990 deaths in 2023. Despite the development of targeted therapies and immunotherapies, many melanomas eventually develop resistance to these treatments. Interestingly, recent studies have identified ADAR1 as a critical factor that regulates resistance to immunotherapy. ADAR1 mediated A-to-I editing of dsRNAs made from repetitive elements spread all over the human genome prevents these dsRNAs from activating interferons and inflammatory responses in tumors, which in turn dampens the responsiveness of tumors to immunotherapy. Furthermore, our own studies suggest that inhibition of ADAR1 enzymatic activity induces accumulation of aberrant R-loops (a form of RNA:DNA hybrid) at the chromosome ends and apoptosis specifically in cancer cells. These recent discoveries suggest that, if ADAR1 activity in tumors could be repressed, this might kill only cancer cells and allow the tumor to be more responsive to immunotherapy. However, no effective drugs to inhibit ADAR1 are currently available. To this end, we have recently identified an ADAR1 inhibitor compound, ADAR1i-124, by high-throughput molecular screening. In this proposal, we explore the potential of ADAR1i-124 as a novel therapeutic to treat melanoma and immunotherapy resistance.

In this MRF 2024 Request for Proposals (RFP) – Established Investigator Awards (EIA) application, we focus on the area of emphasis: Therapy and Resistance and will develop novel therapeutic strategies for the treatment of melanoma and prevention of immunotherapy resistance.

Our objective is to prove our hypothesis that ADAR1 inhibitors hold promise as future therapeutics to treat melanoma and immunotherapy resistance. The outcome of this proposal will have a significant impact on the future treatment of melanoma patients. We expect that these studies will truly have a transformative impact on the management of melanoma for patients impacted by this devasting disease, and their family members as well.