2025 GIGA Annual Report | 19 Melanoma, one of the deadliest skin cancers, remains a major therapeutic challenge due to its ability to develop resistance to targeted therapies, ultimately leading to treatment failure and disease progression. Pierre Close (WELRI Investigator) and his team at the Laboratory of Cancer Signaling investigated the molecular mechanisms underlying this resistance and identified a crucial role for the enzyme VARS (Valyl tRNA synthetase) in sustaining the survival of therapy-resistant melanoma cells. Using protein and RNA sequencing data, the researchers demonstrated that resistant cells undergo a profound reprogramming of their protein synthesis machinery, shifting their reliance onto VARS. By inhibiting this enzyme, they were able to re-sensitize melanoma cells to treatment, effectively reversing resistance. These findings highlight the importance of transfer RNA regulation in acquired drug resistance and suggest that targeting VARS could enhance the efficacy of existing therapies. This discovery paves the way for new treatment strategies aimed at overcoming resistance mechanisms in melanoma, offering fresh hope for patients facing limited therapeutic options. VALINE AMINOACYL-TRNA SYNTHETASE PROMOTES THERAPY RESISTANCE IN MELANOMA El-Hachem N, Leclercq M, Susaeta Ruiz M, Vanleyssem R, Shostak K, Körner PR, Capron C, Martin-Morales L, Roncarati P, Lavergne A, Blomme A, Turchetto S, Goffin E, Thandapani P, Tarassov I, Nguyen L, Pirotte B, Chariot A, Marine JC, Herfs M, Rapino F, Agami R, Close P. p LINKS | News GIGA | Publication on ORBI | Pierre Close Nat Cell Biol. 2024 Jul;26(7):1154-1164. doi: 10.1038/s41556-024-01439-2.
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