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the internal organization of a melanoma cell generated from data acquired by focused ion beam scanning electron microscopyHeymann JAW, Shi D, Kim S, Bliss D, Milne JLS and Subramaniam S. 3D Imaging of Mammalian Cells by Ion Abrasion Scanning Electron Microscopy. J Struct Biol. 2009 April; 166 (1): 1-7. via https://electron.nci.nih.gov/gallery
Melanoma accounts for only about 1% of skin cancers, but is by far the most deadly and has a reputation for rapidly developing resistance to chemotherapy. In addition, melanoma rates have increased in recent decades. In 2019, the American Cancer Society predicts that, in the United States alone, more than 96,000 people will be diagnosed with melanoma and more than 7,000 will die from it.
The risk of melanoma is known to be related to mutations at particular genetic hot spots. In other words, mutations in some genes seem to drive the development of melanoma. In particular, & nbsp;mutations in a gene called NRAS & nbsp;are & nbsp; in about 25% of melanomas, and play a critical role in the development of the tumor.
the NRAS the gene codes for the NRAS protein. The main NRAS The mutations badociated with melanoma are "activating mutations": they cause the activation of the NRAS protein. The problem is that a number of important cellular pathways – including those involved in cell growth, movement, and survival – are gaining ground from the NRAS. So, when NRAS gets stuck in the "on" position, these lanes become deregulated, and this opens the way to tumor growth.
In addition, research has shown that melanomas with NRAS mutations tend to be more aggressive and are more likely to develop resistance to treatment.
It is therefore not surprising that the development of melanoma therapies targeting NRAS is attracting a lot of attention. however, it was difficultpartly because of the aggressive nature of NRAS mutant melanomas.
A representation of the NRAS proteinEmw via Wikimedia commons
But what if you do not have to target the NRAS directly, but you can just get something out of it?
Now, a team of researchers from Boston University, as well as Fudan University and Xiamen University in China, has discovered that the NRAS needs an enzyme called STK19.
Rutao Cui from the Boston University School of Medicine and his colleagues found that STK19 is responsible for starting the NRAS. & Nbsp; It does this by marking it with a small molecule called phosphate. NRAS needs this phosphate, so without STK19, NRAS does not work.
The researchers then designed an inhibitor to block the activity of STK19 and thus prevent it from delivering phosphate molecules. Laboratory tests on skin cell cultures showed that the inhibitor was able to prevent the activation of NRAS and thus blocked the formation of melanomas. This was also the case when they tested the inhibitor on mice: it dramatically reduced the formation of tumors.
"Our results provide a new viable therapeutic strategy for melanomas with NRAS mutations," say the researchers in their new article. published today in the journal Cell.
In addition, STK19 targeting may have potential beyond melanoma.
In humans, NRAS is one of three members of the RAS protein family: HRAS, KRAS and NRAS. This trio shares a high degree of similarity, and mutations in these RAS proteins are present in more than 30% of all cancers in humans. In particular, RAS mutations result in up to 95% of pancreatic cancers and 45% of colorectal cancers.
The authors say that for these cancers and especially for those who develop resistance to other treatments, it is important to explore what blocking STK19 could do.
Original search:
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the internal organization of a melanoma cell generated from data acquired by focused ion beam scanning electron microscopyHeymann JAW, Shi D, Kim S, Bliss D, Milne JLS and Subramaniam S. 3D Imaging of Mammalian Cells by Ion Abrasion Scanning Electron Microscopy. J Struct Biol. 2009 April; 166 (1): 1-7. via https://electron.nci.nih.gov/gallery
Melanoma accounts for only about 1% of skin cancers, but is by far the most deadly and has a reputation for rapidly developing resistance to chemotherapy. In addition, melanoma rates have increased in recent decades. In 2019, the American Cancer Society predicts that in the United States alone, more than 96,000 people will be diagnosed with melanoma and more than 7,000 will die from it.
The risk of melanoma is known to be related to mutations at particular genetic hot spots. In other words, mutations in some genes seem to drive the development of melanoma. In particular, mutations in a gene called NRAS are found in about 25% of melanomas, and play a critical role in the development of the tumor.
the NRAS the gene codes for the NRAS protein. The main NRAS The mutations badociated with melanoma are "activating mutations": they cause the activation of the NRAS protein. The problem is that a number of important cellular pathways – including those involved in cell growth, movement, and survival – are gaining ground from the NRAS. Thus, when NRAS remains stuck in the "on" position, these pathways become deregulated, which opens the way to tumor growth.
In addition, research has shown that melanomas with NRAS mutations tend to be more aggressive and are more likely to develop resistance to treatment.
It is therefore not surprising that the development of melanoma therapies targeting NRAS is attracting a lot of attention. However, this was difficult, in part because of the aggressive nature of mutant NRAS melanomas.
A representation of the NRAS proteinEmw via Wikimedia commons
But what if you do not have to target the NRAS directly, but you can just get something out of it?
Now, a team of researchers from Boston University, as well as Fudan University and Xiamen University in China, has discovered that the NRAS needs an enzyme called STK19.
Rutao Cui of the Boston University School of Medicine and his colleagues discovered that STK19 is responsible for the activation of the NRAS. To do this, it marks NRAS with a small molecule called phosphate. NRAS needs this phosphate, so without STK19, NRAS does not work.
The researchers then designed an inhibitor to block the activity of STK19 and thus prevent it from delivering phosphate molecules. Laboratory tests on skin cell cultures showed that the inhibitor was able to prevent the activation of NRAS and thus blocked the formation of melanomas. This was also the case when they tested the inhibitor on mice: it dramatically reduced the formation of tumors.
"Our results provide a new viable therapeutic strategy for melanoma with NRAS mutations," the researchers say in their new article, published today in the journal. Cell.
In addition, STK19 targeting may have potential beyond melanoma.
In humans, NRAS is one of three members of the RAS protein family: HRAS, KRAS and NRAS. This trio has a high degree of similarity and mutations in these RAS proteins are present in more than 30% of all human cancers. In particular, RAS mutations result in up to 95% of pancreatic cancers and 45% of colorectal cancers.
The authors say that for these cancers and especially for those who develop resistance to other treatments, it is worth exploring what blocking STK19 could do.
Original search:
Yin, C et al. (2019). Pharmacological targeting of STK19 inhibits oncogenic NRAS-induced melanomagenesis. Cell 176, 1-15
