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

ABSTRACT: Uveal melanoma (UM) is a high fatality cancer. It arises in the eye and spreads (metastasizes) to the liver in 50% of affected patients, with a low survival rate of 5 years. In >85% of patients, their ocular tumors have mutations in specific genes, GNAQ and GNA11, leading to tumor progression and metastasis. Conventional therapies such as surgery, chemotherapy, and irradiation halt tumor progression in the eye. Unfortunately, once cancer progresses to metastasis (usually occurring at early stages of the disease), the patients have limited treatment options. Moreover, targeted therapies and immunotherapies fail to achieve more significant survival benefits due to UM's emergence of resistance. Therefore, there is an urgent need to develop new therapeutic strategies to treat UM. This project explores the use of 2 small molecule inhibitors , which suppresses MNK1/2-eIF4E (SEL201) and mTORC1/2-4EBP1 (INK128), as a strategy to block the progression of UM to invasive and metastatic disease. Our data shows that both inhibitors work in concert to decrease clonogenicity and invasiveness of some, but not all, UM cell lines screened. To define the mechanism by which MNK1/2 blockade augments the efficacy of mTOR inhibitors in UM, we performed a discovery approach where T128 UM cells were treated with the drug combination for 24h and sent for DIA MS analysis. The analysis showed that protein vesicle trafficking, driven mainly RAB1A, was being downregulated in the combination treatment, which translated to decreased invasive and clonogenic potential.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Choroidal Melanocyte, Cell Culture

DISEASE(S): Uveal Melanoma

SUBMITTER: Raul Ernesto Flores Gonzalez  

LAB HEAD: Sonia del Rincon

PROVIDER: PXD068873 | Pride | 2026-02-20

REPOSITORIES: Pride