An international research team led by scientists from the University of Liège (Belgium) has discovered an intriguing new therapeutic target for the treatment of melanoma that is resistant to targeted therapies. Inhibition of the VARS enzyme could prevent this therapeutic resistance by re-sensitizing tumors that are resistant to these targeted therapies.
Melanoma is one of the most serious and aggressive forms of skin cancer. When diagnosed early, melanoma is surgically removed. However, once metastases (ie secondary distant tumors) have developed, melanoma becomes difficult to treat, limiting patients’ chances of recovery. Every year in Belgium, around 3,000 people are diagnosed with melanoma. Doctors use targeted therapies to treat skin melanoma patients with a mutation in the BRAF gene – the gene responsible for producing B-Raf, the protein that promotes cancer growth. This mutation is found in over 50% of patients.” explains Pierre Close, researcher at ULiège. While targeted therapies are highly effective in shrinking tumors, almost all patients who use them will develop acquired or secondary resistance to these therapies, which limits long-term therapeutic response.” It is therefore important to understand the mechanisms involved in resistance to targeted therapies in order to develop new therapeutic strategies for melanoma patients.
ARNt and VARS
The team from the Cancer Signaling Laboratory at ULiège, led by Pierre Close, has just made a very interesting discovery in this area. Thanks to the analysis of the collected data, we were able to observe that the adaptation of melanoma cells to targeted therapy was associated with a reprogramming of protein synthesis“, explains Najla El Hachem, the lead researcher from the Belgian Cancer Foundation in Pierre Close’s laboratory. “We combined a number of protein and RNA sequencing approaches and discovered that treatment-resistant cells developed a dependency on certain key factors in protein synthesis by regulating transfer RNAs (tRNAs). These players include the enzyme VARS (Valyl tRNA synthetase), which regulates the aminoacylation – the process by which an amino acid is attached to tRNA – of transfer RNAs and promotes resistance in melanoma cells. Genetic inhibition of VARS therefore prevents therapeutic resistance and re-sensitizes tumors resistant to targeted therapies.
New hope for patients
The promising results of this research pave the way for new treatment combinations for malignant melanoma. This discovery indicates that the regulation of transfer RNAs plays an important role in therapeutic resistance.” enthuses Pierre Close. In addition, inhibition of VARS could enhance the efficacy of targeted therapies and limit the development of treatment resistance. These results could lead to the development of new therapeutic strategies and offer a new ray of hope for patients suffering from resistant melanoma. Researchers will continue their work to turn this discovery into a specific and effective treatment option.
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Journal Reference:
El-Hachem, N., et al. (2024). Valine aminoacyl-tRNA synthetase promotes treatment resistance in melanoma. Nature Cell Biology. doi.org/10.1038/s41556-024-01439-2.
