New Therapeutic Opportunity for Treatment of Malignant Melanoma

A new therapeutic opportunity has been uncovered in the treatment of malignant melanoma that acquired resistance to targeted therapies. Researchers in Belgium have revealed that malignant melanoma can reprogram their protein synthesis machinery and become addicted to a new family of enzymes that modify transfer RNAs during acquired resistance. The inhibition of these molecules synergies with targeted therapies to produce a strong anti-tumoural effect. These new findings will be integral in the development of improved diagnostic tools and melanoma treatment.

Resistance to therapy is the main limitation of current treatment of aggressive cancers such as malignant melanoma. Insurgence of resistance relates to the capability of tumour cells to circumvent the stress induced by the treatment. In order to survive, cancer cells develop a series of adaptation mechanisms through rewiring fundamental processes. Among those, reprogramming of mRNA translation favours the expression of proteins essential for tumour development.

Researchers from the University of Liège have been studying the contribution of wobble tRNA modification in cancer development through regulation of selective mRNA translation for a few years, uncovering their central role in tumour initiation and metastatic potential.

Modification of certain tRNA molecules at the wobble position regulates selective mRNA translation and impact on protein expression. The GIGA-ULiège team discovered that melanoma that carry the BRAF(V600E) mutation – found in more than 50 per cent of the melanoma patients – are addicted to enzymes modifying wobble uridine tRNAs (U34-tRNA).

The research showed that wobble uridine tRNA modification enzymes are upregulated in melanoma clinical samples and very lowly expressed in melanocytes, the normal melanin-producing cells. Inhibition of this family of enzymes led to a very strong and specific cell death in BRAF(V600E) melanoma, but had no effect on melanocytes. This very specific effect led researchers to postulate that these enzymes may play an important role in melanoma development.

Growing melanoma tumours adapt their metabolism and use glucose as a source of energy. The researchers demonstrated that U34-tRNA enzymes are key for the expression of proteins involved in glucose metabolism.

Using melanoma patients derived samples, researchers found that U34-tRNA enzymes are essential to sustain glucose metabolism. Therefore, the inhibition of these enzymes prevents glucose metabolism in melanoma cells, and limits their energy income. As a consequence, the growth and survival of melanoma cells is strongly reduced after inhibition of U34-tRNA enzymes. Acquired resistance to targeted therapy, which strongly limits the clinical benefit of the treatment of malignant melanoma, is prevented by the inhibition of U34-tRNA enzymes. In other words, the inhibition of these enzymes synergises with targeted therapies to block malignant melanoma growth.

This work revealed the clinical potential of U34-tRNA enzymes inhibition for the treatment of human malignant melanoma, a disease that remains extremely difficult to treat. Further research will be necessary to firmly establish the real clinical benefit of this approach and to develop therapeutic tools that could achieve this goal.

Read more recent research on melanoma.

 

Source:
Francesca Rapino, Sylvain Delaunay, Florian Rambow, Zhaoli Zhou, Lars Tharun, Pascal De Tullio, Olga Sin, Kateryna Shostak, Sebastian Schmitz, Jolanda Piepers, Bart Ghesquière, Latifa Karim, Benoit Charloteaux, Diane Jamart, Alexandra Florin, Charles Lambert, Andrée Rorive, Guy Jerusalem, Eleonora Leucci, Michael Dewaele, Marc Vooijs, Sebastian A. Leidel, Michel Georges, Marianne Voz, Bernard Peers, Reinhard Büttner, Jean-Christophe Marine, Alain Chariot, Pierre Close. Codon-specific translation reprogramming promotes resistance to targeted therapyNature, 2018; DOI: 10.1038/s41586-018-0243-7


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