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mapk_pathway_drugs_ocular_toxicity [2026/07/01 22:23] – Scott Larsonmapk_pathway_drugs_ocular_toxicity [2026/07/01 22:29] (current) – Scott Larson
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 ===== The MAPK Cascade ===== ===== The MAPK Cascade =====
 The MAPK/RAS-RAF-MEK-ERK cascade is a highly conserved, three-tiered signaling pathway that transmits extracellular signals from the cell surface to the nucleus, regulating cell proliferation, differentiation, survival, and migration. The MAPK/RAS-RAF-MEK-ERK cascade is a highly conserved, three-tiered signaling pathway that transmits extracellular signals from the cell surface to the nucleus, regulating cell proliferation, differentiation, survival, and migration.
 +[[https://onlinelibrary.wiley.com/cms/asset/62ef33b9-04f0-4739-b255-aaa5a35df3c1/cns14807-fig-0001-m.jpg|Diagram of Pathway]]
  
 ==== Step-by-Step Signal Transduction ==== ==== Step-by-Step Signal Transduction ====
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 Oncogenic mutations — most commonly in KRAS (~30% of all cancers) and BRAF V600E (~7% of all cancers, ~60% of melanomas) — constitutively activate this cascade. Ocular toxicity from MAPK pathway inhibitors arises because ERK signaling is critical for retinal pigment epithelium (RPE) homeostasis; ERK loss in RPE cells leads to decreased RPE65 expression and retinal degeneration. Oncogenic mutations — most commonly in KRAS (~30% of all cancers) and BRAF V600E (~7% of all cancers, ~60% of melanomas) — constitutively activate this cascade. Ocular toxicity from MAPK pathway inhibitors arises because ERK signaling is critical for retinal pigment epithelium (RPE) homeostasis; ERK loss in RPE cells leads to decreased RPE65 expression and retinal degeneration.
  
-===== Eye Diseases Associated With Tovorafenib ===== 
- 
-Tovorafenib (Ojemda), a pan-RAF kinase inhibitor approved for pediatric [low-grade glioma](https://www.openevidence.com/rare-disease/low-grade-astrocytoma), is associated with several ocular adverse events: 
- 
-  * **MEK inhibitor-associated retinopathy (MEKAR)** — serous retinal detachment and retinal pigment epithelium (RPE) changes* 
-  * **Photosensitivity** — patients are advised to wear sunglasses* 
-  * **Periorbital edema*** 
-  * **Blurred vision*** 
- 
-These effects are considered a class effect of MAPK pathway inhibition, particularly due to downstream suppression of ERK signaling in the retinal pigment epithelium. 
  
 ===== Drugs in the MAPK/RAS-RAF-MEK-ERK Pathway With Ocular Toxicity ===== ===== Drugs in the MAPK/RAS-RAF-MEK-ERK Pathway With Ocular Toxicity =====
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 | **Sorafenib** (Nexavar) | Blurred vision, conjunctivitis | First-generation pan-RAF inhibitor; less retinal toxicity than MEK inhibitors | | **Sorafenib** (Nexavar) | Blurred vision, conjunctivitis | First-generation pan-RAF inhibitor; less retinal toxicity than MEK inhibitors |
 | **CH5126766/VS-6766** (investigational, dual RAF-MEK) | RPED (30%), blurred vision/color changes (49%) | Very high ocular toxicity rate due to potent MAPK suppression | | **CH5126766/VS-6766** (investigational, dual RAF-MEK) | RPED (30%), blurred vision/color changes (49%) | Very high ocular toxicity rate due to potent MAPK suppression |
 +
 +=== Eye Diseases Associated With Tovorafenib ===
 +
 +Tovorafenib (Ojemda), a pan-RAF kinase inhibitor approved for pediatric [low-grade glioma](https://www.openevidence.com/rare-disease/low-grade-astrocytoma), is associated with several ocular adverse events:
 +
 +  * **MEK inhibitor-associated retinopathy (MEKAR)** — serous retinal detachment and retinal pigment epithelium (RPE) changes*
 +  * **Photosensitivity** — patients are advised to wear sunglasses*
 +  * **Periorbital edema***
 +  * **Blurred vision***
 +
 +These effects are considered a class effect of MAPK pathway inhibition, particularly due to downstream suppression of ERK signaling in the retinal pigment epithelium.
  
 ==== ERK Inhibitors ==== ==== ERK Inhibitors ====