Related Experiment Video
Updated: Jan 11, 2026
Retinal Pigment Epithelium Transplantation in a Non-human Primate Model for Degenerative Retinal Diseases
Published on: June 14, 2021
Modeling MEK inhibitor-Associated Retinopathy in vitro using human induced pluripotent stem cell-derived retinal
Abstract:
Pharmacologic inhibitors of MEK are important anti-cancer drugs but can result in MEK inhibitor-Associated Retinopathy (MEKAR) in which vision is lost due to serous retinal detachments that form via an unknown mechanism. We hypothesized that the cause of this side effect is drug-induced dysfunction of retinal pigment epithelial (RPE) cells. To test this hypothesis, we used human induced pluripotent stem cell-derived RPE cells. We treated mature, hiPSC-derived RPE cells with selumetinib and measured impacts on RPE-specific function, structure, and gene expression. Selumetinib increases the ability of hiPSC-derived RPE to internalize bovine rod outer segments (1.9 vs 3.0, p=0.0024). It also decreases expression of aquaporin 1 during the first 10 days of treatment (2.7 vs 1.1, p=0.0015). It has no effect on the ability of hiPSC-derived RPE to maintain membrane integrity. Selumetinib alters gene expression of hiPSC-derived RPE, with significant changes in genes involved in transport of ions and small molecules regulating cell volume and lysosomal acidification. Selumetinib may lead to subretinal fluid accumulation by both increasing secretions into this space and decreasing outflow.
Insights
MEK inhibitor-associated retinopathy (MEKAR) may stem from retinal pigment epithelial (RPE) cell dysfunction. Selumetinib treatment in RPE cells altered gene expression and transport, potentially causing fluid buildup and vision loss.
Area of Science:
- Ophthalmology
- Pharmacology
- Cell Biology
Background:
- MEK inhibitors are vital anti-cancer drugs.
- MEK inhibitor-Associated Retinopathy (MEKAR) causes vision loss via unknown mechanisms.
- Retinal pigment epithelial (RPE) cells are crucial for retinal health.
Purpose of the Study:
- To investigate if MEK inhibitors cause MEKAR through RPE cell dysfunction.
- To elucidate the impact of selumetinib on RPE cell function and gene expression.
Main Methods:
- Utilized human induced pluripotent stem cell-derived RPE cells.
- Treated mature RPE cells with selumetinib.
- Assessed RPE function, structure, and gene expression.
Main Results:
- Selumetinib enhanced RPE cell internalization of rod outer segments.
- Decreased aquaporin 1 expression was observed.
- Significant alterations in genes related to ion transport and cell volume regulation were found.
- No impact on RPE membrane integrity.
Conclusions:
- MEK inhibitor-induced RPE cell dysfunction may cause MEKAR.
- Selumetinib may promote subretinal fluid accumulation by altering RPE transport and secretion.
- Further research is needed to fully understand MEKAR pathogenesis.
