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New therapeutic target discovered for the treatment of therapy-resistant melanoma
Last reviewed: 02.07.2025
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An international team of researchers led by scientists from the University of Liege (Belgium) has identified a promising therapeutic target for the treatment of melanoma resistant to targeted therapy. Inhibition of the VARS enzyme can prevent resistance to treatment, re-sensitizing tumors previously resistant to targeted therapy.
Melanoma: Challenges and Current Treatments
Melanoma is one of the most serious and aggressive forms of skin cancer. When detected early, melanoma is removed surgically. However, when metastases (secondary tumors) develop, melanoma treatment becomes challenging, reducing the chances of cure. Every year, around 3,000 people are diagnosed with melanoma in Belgium. To treat patients with a mutation in the BRAF gene, which is responsible for the production of the B-Raf protein, which promotes cancer, doctors use targeted therapies. This mutation occurs in more than 50% of patients, explains Pierre Cloz, a researcher at ULiège. Although targeted therapies are effective in shrinking tumors, almost all patients develop acquired or secondary resistance to these therapies, which limits the long-term therapeutic response. It is therefore important to understand the mechanisms of resistance to targeted therapies in order to develop new treatment strategies for patients with melanoma.
ARNt and VARS
A team from the Laboratory of Cancer Signalling Pathways at ULiège, led by Pierre Clos, has made an important discovery in this area. "By analysing the data we collected, we discovered that the adaptation of melanoma cells to targeted therapy is linked to a reprogramming of protein synthesis," explains Najla El Hachem, lead researcher at the Belgian Cancer Foundation in the Laboratory of Pierre Clos. "We used different protein and RNA sequencing techniques and found that cells resistant to therapy had developed a dependence on certain key elements of protein synthesis that regulate transfer RNAs (tRNAs)." These elements include the enzyme VARS (valyl-tRNA synthetase), which regulates aminoacylation - the process of attaching an amino acid to a tRNA - and contributes to the resistance of melanoma cells. Genetic inhibition of VARS prevents resistance to therapy and re-sensitises tumours resistant to targeted therapy.
New hope for patients
The results of this study open the way for new combinations of treatments for malignant melanoma. "This discovery shows that the regulation of transfer RNAs plays an important role in therapeutic resistance," says Pierre Cloz enthusiastically. "Inhibition of VARS could improve the effectiveness of targeted therapies and limit the development of resistance to treatment. These results could lead to the development of new therapeutic strategies and offer a new ray of hope for patients suffering from resistant melanoma." The researchers will continue their work to turn this discovery into a concrete and effective therapeutic option.
The results of the study were published in the journal Nature Cell Biology.