Melanoma is a type of skin cancer that accounts for 1% of all skin cancer cases. Despite this small percentage, melanoma is responsible for a large number of skin cancer deaths. According to the American Cancer Society, over 96,000 people in the United States will develop melanoma in 2019, and more than 7,000 will die as a result. A mutation in a gene that scientists call N-Ras causes one form of melanoma to be particularly aggressive. N-Ras mutation status was identified as an independent predictor of shorter survival after a diagnosis of stage IV melanoma. Melanoma with N-Ras mutations accounts for 20-30% of all melanoma cases. Patients with N-Ras Q61K mutations have a higher incidence of central nervous system metastasis at the time of diagnosis of stage IV disease, compared to patients who are wild-type for N-RAS. Normally, the N-Ras gene encodes a protein of the same name that is mainly involved in regulating cell division. However, N-Ras is an oncogene, meaning that when it mutates, it has the ability to turn normal cells into cancerous cells. Other than N-Ras, there are other Ras proteins having a role in signal transduction. K-Ras and H-Ras have been the most studied, since are involved in most of the types of human cancers.
New research may have found a drug compound that could fight off this type of skin cancer, right targeting the N-Ras signaling. Dr Rutao Cui, a Boston University School of Medicine professor of Pharmacology and Dermatology, is the last and corresponding author of the study. Prof. Cui explains the motivation for the research: “There are immunotherapies and targeted therapies that have shown huge improvements for patients with melanoma. However, for patients with N-Ras mutations, there are not very effective treatment strategies”. In the search for such an effective treatment, the researchers examined the chain reaction of genes — and their respective proteins — that trigger melanoma with N-Ras mutations. N-Ras acts like a genetic switch that is, in turn, turned on and off by other molecules. GTP-bound N-Ras activates signaling cascades via binding and stimulating downstream effectors such as c-Raf, PI-3-Kinase and PLC, whereas the GDP-bound form of RAS is inactive. Until now researchers did not know precisely which proteins trigger N-Ras. However, after performing a series of experiments where they tested the effect of various proteins on N-Ras activity, the scientists narrowed their search down to a protein called STK19.
Alterations in the gene that encodes STK19 were present in 25% of all human melanomas. It is a protein kinase, meaning it modify proteins changing their catalytic activity. STK19 phosphorylates N-Ras to enhance its binding to its downstream effectors and promotes oncogenic NRAS-mediated melanocyte malignant transformation. They believe that STK19 switches N-Ras on, which, in turn, activates downstream proteins and finally other genes. Importantly, unlike N-Ras, scientists could easily deactivate STK19. They designed an STK19 inhibitor called ZT-12-037-01 and tested it both in vitro and in vivo. Both cell cultures and animal models revealed that the compound can inhibit N-Ras and stop melanoma from growing. Next, Prof. Cui and team plan to test their compound with human clinical trials, hopefully, proving that the compound is effective in humans. Prof. Cui concluded: “Together, our findings provide a new and viable therapeutic strategy for melanomas, harboring N-Ras mutations. We need more monitoring for early diagnosis and full-body examinations for problematic spots, and more proactive strategies for patients at the highest risk of developing melanoma to prevent cancer progression and metastasis.”
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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