An international research team led by scientists from the GIGA Institute of the University of Liège has discovered an interesting new therapeutic target for the treatment of melanomas resistant to targeted therapies. Inhibition of the VARS enzyme could prevent this therapeutic resistance by resensitizing tumors resistant to these targeted therapies.
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Melanoma is one of the most serious and aggressive forms of skin cancer. When diagnosed early, melanoma is removed by surgical excision. However, after the appearance of metastases (tumors formed from cancer cells), melanoma becomes difficult to treat, which limits patients’ chances of recovery. Every year in Belgium, around 3,000 people are diagnosed with melanoma. Doctors use targeted therapies* to treat patients with cutaneous melanoma who have a mutation in the BRAF gene – the gene responsible for the production of B-Raf, the protein that promotes the occurrence of cancer. “This mutation is found in more than 50% of patients, explains Pierre Close, FNRS Research Master and WELBIO Investigator at ULiège. While targeted therapies are very effective in reducing tumors, almost all patients who use them will develop acquired or secondary resistance to these therapies, which limits the long-term therapeutic response.” It is therefore crucial to understand the mechanisms involved in resistance to targeted therapies in order to develop new therapeutic strategies for melanoma patients.
tRNA and VARS
The team from the Cancer Signaling Laboratory (GIGA Institute) at ULiège, led by Pierre Close, has just made a very interesting discovery in this area. “Thanks to the analysis of the data collected we were able to observe that the adaptation of melanoma cells to targeted therapy was associated with a reprogramming of protein synthesisexplains Najla El Hachem, researcher at the Cancer Foundation in the cancer signaling laboratory. “We combined numerous protein and sRNA sequencing approaches and discovered that therapy-resistant cells developed a dependence on certain essential players in protein synthesis, regulating transfer RNAs (tRNAs).” Among these players is the enzyme called VARS (Valyl tRNA synthetase), which regulates aminoacylation – the process by which an amino acid attaches to tRNA – of transfer RNA and promotes the resistance of melanoma cells. Genetic inhibition of VARS therefore prevents therapeutic resistance and resensitizes tumors resistant to targeted therapies.
New hope for patients
The promising results of this research pave the way for new treatment combinations for malignant melanomas. “This discovery shows that the regulation of transfer RNA plays an important role in therapeutic resistance, rejoices Pierre Close. Furthermore, inhibition of VARS could enhance the effectiveness of targeted therapies and limit the emergence of treatment resistance.” Results which could be at the origin of the implementation of new therapeutic strategies and which offer a new glimmer of hope for patients suffering from resistant melanomas. Researchers will continue their work to transform this discovery into a concrete and effective therapeutic option.
© Adeline Deward (Illumine)
Therapeutic resistance of melanomas is associated with reprogramming of tRNAs and protein translation, which represents a new vulnerability of resistant melanomas, and a new opportunity to develop new treatments. Credit: Adeline Deward (Illumine)
* Targeted therapies are new forms of cancer treatment that exploit the biological differences that exist between cancer cells and healthy cells in the body.
Scientific reference
Najla El-Hachem, Marine Leclercq, Miguel Susaeta Ruiz, Raphael Vanleyssem, Kateryna Shostak, Pierre-René Körner, Coralie Capron, Lorena Martin-Morales, Patrick Roncarati, Arnaud Lavergne, Arnaud Blomme, Silvia Turchetto, Eric Goffin, Palaniraja Thandapani, Ivan Tarassov, Laurent Nguyen, Bernard Pirotte, Alain Chariot, Jean-Christophe Marine, Michael Herfs, Francesca Rapino, Reuven Agami & Pierre Close, Valine aminoacyl-tRNA synthetase promotes therapy resistance in melanoma, Nature Cell Biology. https://doi.org/10.1038/s41556-024-01439-2
Your contacts at ULiège
Pierre Close
Najla El-Hachem
