Treating melanoma by turning off a common mutation

Mutations in the NRAS gene account for about 25% of melanoma cases. But so far, drugs designed to rein in the rogue NRAS protein have yielded little success. Now, a Boston University-led team of scientists has pinpointed an enzyme that regulates NRAS activation and developed a drug that prevented melanoma growth in mouse models.

The activator is called STK19, and it works by "phosphorylating," or altering the structure of the NRAS protein to turn on its cancer-causing effect, according to the team. In a new study published in Cell, the researchers demonstrated how the drug candidate they developed inhibited STK19 and hence melanoma development, offering a promising new option to treat the deadliest type of skin cancer.

RAS proteins play a key role in the regulation of cell growth and survival. When they become overactive, cancer can develop. Some RAS signaling pathways are already popular targets in cancer research, including those that involve RAF-MEK-ERK and PI3K.

NRAS is one of three members of the RAS family, and previous studies have shown that mutations in the gene can cause melanoma. To find the culprit behind such oncogenic activation, the BU-led team screened for enzymes that could regulate the activity of a prevalent melanoma-causing NRAS mutation.

Among all the enzymes they scanned, STK19 stood out: Knocking it down led to the greatest inhibition of NRAS. In human melanoma samples depleted of STK19, NRAS activity dropped significantly, and when the cells were reinfected with STK19, NRAS signaling returned, the team reported.

In contrast to fast advancement in medical research on BRAF-mutant melanoma, little progress has been made in developing therapeutics against NRAS-mutant forms of the skin cancer. Array BioPharma, for example, has already won FDA approval for its BRAF-MEK combo therapy Braftovi and Mektovi to treat melanoma. However, it chose to withdraw an application for its late-stage candidate binimetinib in NRAS-mutant melanoma after the FDA asked for more data.

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The BU-led researchers believe their findings provide a new opportunity to expand the selection of disease-modifying melanoma treatments. “Given the pivotal role of NRAS signaling ... and the prominent role of STK19 in NRAS activation, targeting STK19 would represent a potential new therapeutic strategy in melanoma, especially in those with NRAS mutations,” the researchers wrote in the study.

They have already selected and refined a small molecule targeting STK19. The drug, dubbed ZT-012-037-1 (1a), significantly inhibited mutant NRAS-STK19-driven melanoma cell formation and tumor development. It also helped prolong the survival of mouse models of the disease, the team reported.

Although the current study focused on NRAS, the scientists noted that the key site of NRAS phosphorylation is also present in the other two RAS proteins. Therefore, targeting STK19 might be a therapeutic option not just for NRAS-driven melanoma, but “in 25% of all cancers with RAS mutations,” the study’s leader Rutao Cui said in a statement. “We hope our findings ultimately will be clinically translated into improved care for cancer patients."