Melanoma, the most serious form of skin cancer, can be treated if it's detected early, but addressing advanced forms of the disease has proven challenging. Researchers at Ludwig Maximilians-Universität in Munich believe they've pinpointed two pathways in the body that prime melanoma cells for death, possibly inspiring new ideas for drug development.
The researchers discovered that a viral RNA-sensing protein called RIG-I preps skin tumors for cell death by activating the production and discharge of inflammatory molecules known as type I interferons, which are small proteins critical to cell signaling. Once that happens, enzymes that cleave RNA, known as RNase L, start destroying cells in the tumors. They published their findings in Science Immunology.
In tumor cells, the scientists found that stimulating RIG-I with a ligand called 3p-RNA produced interferons. But if interferon signaling was blocked, the cells didn't die. Cells that lacked RNase L but had plenty of RIG-I also failed to undergo cell death.
Importantly, these two pathways are druggable, tightly connected and regulated, the researchers found. So drugs designed to dial them up would be unlikely to harm healthy cells, they believe.
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In fact, Merck is already working on a drug to target the RIG-1 pathway in cancer.
Merck picked up a RIG-1 agonist in a $137 million acquisition of German biotech Rigontec in September 2017 but has struggled to move it forward in clinical trials. The company tested the drug, dubbed MK-4621, in patients with advanced or recurrent tumors but ended up halting the trial. In a May 2019 report, the company said the study was ditched early due to “program prioritization and not related to any safety concerns.”
In March of this year, Merck completed another trial in patients with solid tumors, testing MK-4621 as both a monotherapy and in combination with Keytruda, its blockbuster PD-1 inhibitor. The company did not respond by press time to questions regarding timing of trial results or plans to explore melanoma as an indication for the treatment.
Several research groups are exploring different methods for targeting RNA in cancer. For example, a Scripps Research Institute team in 2018 unleashed cell death in triple-negative breast cancer cells by tethering RNase L to a molecule they created to bind with miRNA-96, a microRNA that promotes cancer cell multiplication. The treatment cleaved the miRNA-96 precursor, killing the cancer cells but not the healthy breast cells.
The Ludwig Maximilians-Universität researchers believe their new study shows how innate immunity could be exploited to treat melanoma and potentially other tumor types. "This two-step mechanism consisting of priming and effector phases" of tumor cell death "appears to be a common mechanism in innate immunity allowing the cell to either cope or perish depending on the insult taken," the German team wrote in the study. "In addition, as both pathways are 'druggable,' a detailed understanding of the molecular mechanisms may pave the way for the development of novel anticancer drugs inducing immunogenic cell death."