Loss of MAPK Pathway Activation in Post-Mitotic Retinal Cells as Mechanism in MEK Inhibition-Related Retinopathy in Cancer Patients

Abstract

Recently, treatment with MEK inhibitors has been shown to be an effective treatment option for metastatic melanoma. Treatment efficacy is dependent on inhibition of MAPK-related melanoma proliferation. However, targeting of MEK can be accompanied by a time-dependent and reversible serous retinopathy of unknown origin.We analyzed the molecular mechanism by which the MEK inhibitor binimetinib may lead to retinopathy, using neuroretina and cell models of retinal pigment epithelium (RPE).Binimetinib inhibited the MAPK pathway while discontinuation of treatment resulted in reactivation. However, cell proliferation was not inhibited correspondingly during binimetinib treatment of ARPE19 cells. Remarkably, post-mitotic neuroretinal tissue displayed a strong MAPK activation that was lost after binimetinib treatment.We propose that binimetinib-associated retinopathy is correlated with inhibition of the MAPK pathway in multiple retinal components. Retinal cells are able to regain the activation after binimetinib treatment, mimicking the reversibility of the retinopathy. As most retinal cells are nonregenerating, other mechanisms than stimulation of proliferation must be involved.

The Oxidative Stress and Mitochondrial Dysfunction during the Pathogenesis of Diabetic Retinopathy

“…Additionally, it can activate NADPH enzyme levels as well, thus increasing the production of ROS and directly damaging endothelial cells [ 55 , 56 ]. Previously, ANG-II was reported to induce the production of peroxynitrite in vascular endothelial cells and to promote PARP signaling activation, which in turn activates NF- κ B and a release of many inflammatory cytokines, leading to the endothelial cell damage [ 57 , 58 ]. These ANG-II effects can be prevented by the use of NADPH oxidase inhibitors [ 59 , 60 ].…”

Pimasertib‐associated ophthalmological adverse events

“…Serous The exact pathogenesis of both serous retinopathy and RVO associated with MEK inhibitor treatment is as yet unclear. In a cell model of RPE and neuroretina, binimetinib administration resulted in inactivation of the MAPK pathway, and discontinuation of administration of the MEK inhibitor binimetinib led to reactivation, mimicking the mild and reversible retinopathy (van Dijk et al 2016). We described this specific phenotype by a mildly symptomatic, time-dependent and reversible accumulation of both foveal and extrafoveal serous SRF, with abnormalities on electro-oculography but without any evidence of choroidal abnormalities (van Dijk et al 2015).…”

“…In addition, anti-RPE and antiretinal autoantibodies may play a role (van Dijk et al 2015). In a cell model of RPE and neuroretina, binimetinib administration resulted in inactivation of the MAPK pathway, and discontinuation of administration of the MEK inhibitor binimetinib led to reactivation, mimicking the mild and reversible retinopathy (van Dijk et al 2016). The occurrence of an RVO, during the prescription of MEK inhibition, has also been described previously in up to 5% of patients (LoRusso et al 2010;Houede et al 2011;Leijen et al 2012 an increase in inflammatory and oxidative stress response, endothelial and blood-retinal barrier damage, and effects on blood coagulation, possibly characteristic for RVO (Huang et al 2009).…”

Ocular Toxicity of Mitogen-Activated Protein Kinase Inhibitors

“…2 Raising the price of older drugs seems particularly objectionable when one considers that the outlay for research and development occurred long ago, and has almost certainly already been recouped, 2 and it raises the question of how older drugs should be priced and valued. 3 Whether and to what degree examples like pyrimethamine represent a common problem or exceptional cases remains unknown. Using Medicare data available for Part B, we sought to analyze the change in average sales price of cancer drugs between January 2010 and January 2015, and whether older drugs were more likely to undergo price increases than newer drugs.…”

“…Results | Seven of 40 patients (18%) developed ocular adverse effects. In the MEKI A group, 3 of 11 patients (27%) developed bilateral central serous chorioretinopathy (CSC) ( Figure, 3 propose that this retinopathy correlates with inhibition of the mitogen-activated protein kinase pathway in multiple retinal components.…”