Novel therapeutic opportunity for the treatment of resistant malignant melanoma
A team of researchers led by Dr Pierre Close, WELBIO investigator of the GIGA Institute from ULIEGE and Dr Francesca Rapino (ULIEGE) has uncovered a novel therapeutic opportunity in the treatment of melanoma that acquired resistance to targeted therapies.
In collaboration with researchers from VIB, they have revealed that malignant melanomas reprogram their protein synthesis machinery and become addicted to a new family of enzymes that modify transfer RNAs during acquired resistance. Strikingly, the inhibition of these molecules synergies with targeted therapies to produce a strong anti-tumoral effect. The new findings, published in the leading scientific journal NATURE, will be key in the development of improved diagnostic tools and melanoma treatment.
Resistance to therapy is the principal limitation of current treatment of aggressive cancers such as malignant melanoma. Insurgence of resistance relates to the capability of tumor 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 favors the expression of proteins essential for tumor development. The lab of Dr. Close has been studying the contribution of wobble tRNA modification in cancer development through regulation of selective mRNA translation for a few years now, uncovering their central role in tumor initiation and metastatic potential.
Malignant Melanoma are addicted to wobble tRNA modification enzymes
Modification of certain tRNA molecules at the wobble position regulates selective mRNA translation and impact on protein expression. The GIGA-ULIEGE team discovered that melanoma that carry the BRAF(V600E) mutation, found in more than 50% of the melanoma patients, are addicted to enzymes modifying wobble uridine tRNAs (U34-tRNA).
Francesca Rapino, post-doctoral researcher in Dr Close’s lab: “Our 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. Strikingly, inhibition of this family of enzymes led a very strong and specific cell death in BRAF(V600E) melanoma, but had no effect melanocytes. This very specific effect led us to postulate that these enzymes may play an important role in melanoma development”
U34-tRNA enzymes regulate melanoma cells metabolism and promote melanoma resistance to targeted therapy
Growing melanoma tumors adapt their metabolism and use glucose (sugar) as source of energy. The ULIEGE scientists demonstrated that U34-tRNA enzymes are key for the expression of proteins involved in glucose metabolism.
Pierre Close (WELBIO, ULIEGE): “Using melanoma patients derived samples, we 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. Strikingly, we discovered that 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 synergizes with targeted therapies to block malignant melanoma growth”.
Newt steps for clinical application
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.
Codon-specific translation reprogramming promotes resistance to targeted therapy. Francesca Rapino et al. Nature. 2018.
Dr Pierre Close, Laboratory of Cancer Signaling, GIGA Institute, University of Liège, Avenue de l'Hôpital 1, Bât. B34, 4000 Liège, Belgium
This work received essential financial support from the following agencies:
- Belgian Foundation Against Cancer (FAF-F/2016/840)
- WELBIO (WELBIO-CR-2017S-02)
- FNRS (MIS F:4532.13)
- ULIEGE (ARC-tRAME)
- TELEVIE (7.4503.14)
- Centre Anticancéreux du CHU de LIEGE
Pr. Alain Chariot – GIGA Institute, ULiege.
Pr. Jean-Christophe MARINE – VIB – KUL Leuven
Pr. Reinhard Büttner – UniKlinik Köln, Germany
Pr. Marc Vooijs – University of Maastricht, The Nederlands
Pr. Michel Georges – GIGA Institute, ULiege.
Dr. Sebastian Leidel – Max Planck Institute Muenster, Germany
Pr. Guy Jerusalem – CHU LIEGE, ULiege.
Drs. Bernard Peers & Marianne Voz – GIGA Institute, ULiege.
Dr. Pascal De Tullio – CIRM Institute, ULiege.