Even though it accounts for only a fraction of all skin cancers, melanoma has a particularly poor prognosis and is responsible for most of the estimated 7,000 related fatalities. The fact that it can quickly develop resistance to chemotherapy makes it especially concerning seeing as rates for the disease have been steadily increasing over the past decades.
One of the main causes of melanoma is mutations in the NRAS gene, found in 25% of cases. These “activating mutations” force the NRAS protein to turn on and remain active. Many important cellular pathways, including those involved in cell growth, movement and survival depend on this gene. As the pathway becomes dysregulated, it opens the door for tumor growth. The resulting melanomas with NRAS mutations are often more aggressive and difficult to treat.
Now, a team of researchers from Boston University working with colleagues from Fudan University and Xiamen University in China, have made an important discovery. It’s actually an enzyme called STK19 that switches NRAS on, in the presence of phosphate.
The team designed an inhibitor to prevent NRAS activation and laboratory testing demonstrated its effectiveness. Dubbed ZT-12-037-01, the compound was able to suppress NRAS from turning on and blocked the formation of melanoma tumors.
“This study provides a promising therapeutic strategy for melanoma treatment. Furthermore, the STK19 inhibitor might be a therapeutic option in 25 percent of all cancers with RAS mutations”, noted corresponding author Rutao Cui, MD, Ph.D., professor of Pharmacology & Experimental Therapeutics. “We hope our findings ultimately will be clinically translated into improved care for cancer patients”.
The RAS family includes three members: HRAS, KRAS, and NRAS. The genes making up this trio are very similar and subsequent mutations in these proteins are found in more than 30% of all human cancers. In fact, RAS mutations are at the root of 95% of pancreatic cancers and 45% of colorectal cancers.
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