A context-dependent modulatory role for eIF6 in acquired resistance to vemurafenib in melanoma.

Abstract

Acquired resistance to vemurafenib, a BRAFV600E-targeted therapy, remains a major challenge in melanoma. The translation initiation factor eIF6 has been implicated in cancer; however, its role in vemurafenib resistance is poorly understood. We investigated eIF6 using melanoma cell lines with distinct mutational backgrounds. RNA sequencing of a resistant cell line revealed dysregulation of MAPK, PI3K-AKT, metabolic, and ribosome biogenesis pathways together with increased eIF6 expression and alterations in translation-related signaling. Silencing of eIF6 led to reduced proliferation and partially restored vemurafenib sensitivity, while its overexpression increased sensitivity irrespective of BRAF status via mTOR and MAPK modulation. These findings reveal a context-dependent role for eIF6, linking translation regulation to therapeutic response in melanoma.