The Impact of Spliceosome Inhibition in SF3B1-Mutated Uveal Melanoma

Overview

Journal Invest Ophthalmol Vis Sci

Specialty Ophthalmology

Date 2024 Oct 7

PMID 39374010

Authors

Josephine Q N Nguyen

Wojtek Drabarek

Aisha M C H J Leeflang

Tom Brands

Thierry P P van den Bosch

Robert M Verdijk

Harmen J G van de Werken

Job van Riet

Dion Paridaens

Annelies de Klein

Erwin Brosens

Emine Kilic

Affiliations

Soon will be listed here.

Abstract

Purpose: Unfortunately, treatment of patients with uveal melanoma (UM) with metastatic disease is limited. Twenty percent of patients with UM harbor a mutation in the splicing factor gene SF3B1, suggesting that aberrant spliceosome function plays a vital role in tumorigenesis. Splicing inhibitors exploit the preferential sensitivity of spliceosome-compromised leukemic cells to these compounds.

Methods: We studied the effect of the splicing inhibitor E7107 using two UM cell lines and ex vivo cultured SF3B1- and BAP1-mutated primary UM tumor slices. These UM cell lines and ex vivo tumor slices were exposed for 24 hours to different concentrations of E7107. Tumor slices were stained with hematoxylin and eosin (H&E) and incubated with BAP1, MelanA, MIB-1, and caspase-3 antisera.

Results: The E7107-exposed UM cell lines exhibited decreased cell viability and increased apoptosis, with the greatest effect on SF3B1-mutated UM cells. A similar effect on UM tumor slices was observed upon exposure to E7107. Additionally, RNA was isolated for differential isoform expression analysis. No significant difference in isoform usage was found genome-wide. However, specific genes were differentially expressed after E7107 treatment in the SF3B1-mutated samples. Moreover, E7107 had the greatest effect on intron retention.

Conclusions: This study indicates/suggests that mutated SF3B1 UM cells are more sensitive to the splicing inhibitor E7107 than wild-type SF3B1 UM cells.

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