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March 7th, 2025
Version: 2
McGill University
cancer biology
biorxiv

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

Flores Gonzalez, R. E.Open in Google Scholar•Goncalves, C.Open in Google Scholar•Wirasinghe, N.Open in Google Scholar•Gaudeault, V.Open in Google Scholar•Noda Ferro, J. M.Open in Google Scholar•Coutant, K.Open in Google Scholar•Mitchell, A.Open in Google Scholar•Guettler, E.Open in Google Scholar•Gonzalez Moreno, D. R.Open in Google Scholar•Preston, S.Open in Google Scholaret al.

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. Proteomic analyses reveal that combined MNK1/2 and mTOR inhibition disrupts Golgi homeostasis and protein vesicle trafficking mainly due to downregulated RAB1A expression, a master regulator of intracellular protein transport. Experimental UM liver metastasis assays show that the knockdown of RAB1A blocks metastasis, a result that is recapitulated by combined pharmacologic inhibition of MNK1/2 and mTOR. 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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