RAB1A is a novel vulnerability in uveal melanoma revealed by dual inhibition of MNK1/2 and mTOR

Uveal melanoma (UM) is an eye cancer that is fatal upon metastasis to the liver. Most treatments trialed in UM fail to provide therapeutic benefit; thus, there is an urgent need for novel treatment strategies. The MAPK and PI3K signaling pathways, key molecular drivers found to be hyper-activated in UM, converge on the MNK1/2-eIF4E and mTORC1/2-4EBP axes. Here, we demonstrate that the pharmacologic inhibition of MNK1/2 in combination with an mTOR inhibitor impairs clonogenic outgrowth and UM cell invasion. Using proteomic analyses, we reveal that combined MNK1/2 and mTOR inhibition disrupts ER-to-Golgi protein vesicle trafficking mainly due to downregulated RAB1A expression, a master regulator of intracellular protein transport. We further uncover that the knockdown of RAB1A blocks liver metastasis, a result that is recapitulated by combined pharmacologic inhibition of MNK1/2 and mTOR. Finally, we show that RAB1A expression reshapes the surfaceome by increasing the abundance of plasma membrane proteins associated with poor overall survival in UM, highlighting its potential as a biomarker. This study identifies protein vesicle transport as an unrecognized vulnerability in UM and supports a mechanistic rationale for targeting MNK1/2 and mTOR in metastatic UM.

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Publication Details

Journal
Cell Death and Differentiation
Published
2026-02-18
DOI
https://doi.org/10.1038/s41418-026-01684-y
Primary Topic
Ocular Oncology and Treatments
Type
article
Field-Weighted Citation Impact
0.00

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article

RAB1A is a novel vulnerability in uveal melanoma revealed by dual inhibition of MNK1/2 and mTOR

Kelly Coutant, Christophe Gonçalves, Natascha Gagnon, José Ferro et al.
Cell Death and Differentiation
Ocular Oncology and Treatments
article

RAB1A is a novel vulnerability in uveal melanoma revealed by dual inhibition of MNK1/2 and mTOR

Kelly Coutant, Christophe Gonçalves, Natascha Gagnon, José Ferro, Samuel E.J. Preston, Véronique Gaudreault, Y. G. Cho, Daniel Moreno, Elizabeth M. Guettler, Theodore Papadopoulos, W L Miller, Solange Landreville, Sonia Victoria Del Rincon, Steve Jean, Feiyang Cai, R. Gonzalez, Noah Wirasinghe, Andrew Mitchell
article en

Abstract

Uveal melanoma (UM) is an eye cancer that is fatal upon metastasis to the liver. Most treatments trialed in UM fail to provide therapeutic benefit; thus, there is an urgent need for novel treatment strategies. The MAPK and PI3K signaling pathways, key molecular drivers found to be hyper-activated in UM, converge on the MNK1/2-eIF4E and mTORC1/2-4EBP axes. Here, we demonstrate that the pharmacologic inhibition of MNK1/2 in combination with an mTOR inhibitor impairs clonogenic outgrowth and UM cell invasion. Using proteomic analyses, we reveal that combined MNK1/2 and mTOR inhibition disrupts ER-to-Golgi protein vesicle trafficking mainly due to downregulated RAB1A expression, a master regulator of intracellular protein transport. We further uncover that the knockdown of RAB1A blocks liver metastasis, a result that is recapitulated by combined pharmacologic inhibition of MNK1/2 and mTOR. Finally, we show that RAB1A expression reshapes the surfaceome by increasing the abundance of plasma membrane proteins associated with poor overall survival in UM, highlighting its potential as a biomarker. This study identifies protein vesicle transport as an unrecognized vulnerability in UM and supports a mechanistic rationale for targeting MNK1/2 and mTOR in metastatic UM.

Cell Death and Differentiation
Université de Sherbrooke (CA), McGill University Health Centre (CA), Centre Hospitalier Universitaire de Sherbrooke (CA), Université Laval (CA), McGill University (CA)
Pfizer, Université Laval, Cancer Research Society, Fondation des Maladies de l'Oeil, Canadian Liver Foundation, Mitacs, Centre Hospitalier Universitaire de Québec, Merck Canada, Canadian Institutes of Health Research, Fonds de Recherche du Québec - Santé, Lady Davis Institute for Medical Research
No poverty
Openalex Percentile: Top 52%
Ocular Oncology and Treatments
DOIOpen Access PDFOpenAlex
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