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mapk_pathway_drugs_ocular_toxicity [2026/07/01 22:16] – [References] Scott Larsonmapk_pathway_drugs_ocular_toxicity [2026/07/01 22:29] (current) – Scott Larson
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 ====== MAPK Pathway Drugs and Ocular Toxicity ====== ====== MAPK Pathway Drugs and Ocular Toxicity ======
 +**MAPK** stands for **Mitogen-Activated Protein Kinase**. The name reflects the pathway's original discovery as a kinase cascade activated by mitogens — extracellular signals (such as growth factors) that stimulate cell division (mitosis).
  
-===== Eye Diseases Associated With Tovorafenib =====+===== 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. 
 +[[https://onlinelibrary.wiley.com/cms/asset/62ef33b9-04f0-4739-b255-aaa5a35df3c1/cns14807-fig-0001-m.jpg|Diagram of Pathway]]
  
-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:+==== Step-by-Step Signal Transduction ====
  
-  * **MEK inhibitor-associated retinopathy (MEKAR)** — serous retinal detachment and retinal pigment epithelium (RPE) changes* +  - **Extracellular stimulus → Receptor activation:** Growth factors bind to receptor tyrosine kinases (RTKs) such as EGFR, triggering receptor dimerization and autophosphorylation. 
-  * **Photosensitivity** — patients are advised to wear sunglasses* +  - **Adaptor protein recruitment → RAS activation:** Phosphorylated RTKs recruit adaptor proteins (Shc, Grb2) and the guanine nucleotide exchange factor SOS, which converts RAS from inactive (RAS-GDP) to active (RAS-GTP). Three RAS isoforms exist: HRAS, KRAS, and NRAS. 
-  * **Periorbital edema*** +  - **RAS → RAF (MAP3K tier):** Active RAS-GTP recruits RAF kinases (ARAF, BRAF, CRAF) to the plasma membrane for activation. BRAF is the most potent activator and the most frequently mutated in cancer (V600E). 
-  * **Blurred vision***+  - **RAF → MEK (MAP2K tier):** Activated RAF phosphorylates MEK1/2. MEK is the only known physiological substrate of RAF. 
 +  - **MEK → ERK (MAPK tier):** Activated MEK1/2 phosphorylate ERK1/2 at the conserved TEY motif. Both phosphorylation events are required for full activation. 
 +  - **ERK → Downstream effectors:** ERK1/2 phosphorylate over 250 known substrates in the cytoplasm and nucleus, activating transcription factors (Elk-1, c-Fos, c-Myc, AP-1) that drive cell cycle progression. 
 + 
 +==== Key Regulatory Features ==== 
 + 
 +  * **Signal amplification:** Each tier amplifies the signal from upstream to downstream 
 +  * **Negative feedback:** ERK phosphorylates upstream components (SOS, RAF) to attenuate signaling 
 +  * **Scaffold proteins** (KSR1/2, IQGAP1, MP1) organize cascade components into signaling complexes 
 +  * **Crosstalk:** Cross-communication with the PI3K/AKT pathway and other MAPK cascades (JNK, p38) 
 + 
 +==== Relevance to Cancer and Ocular Toxicity ==== 
 + 
 +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.
  
-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 ====
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 ==== Key Patterns by Pathway Target ==== ==== Key Patterns by Pathway Target ====
  
-  * **MEK inhibitors** carry the highest ocular risk (MEKAR, serous retinopathy, RVO), occurring in up to 90% of patients on subclinical OCT* +  * **MEK inhibitors** carry the highest ocular risk (MEKAR, serous retinopathy, RVO), occurring in up to 90% of patients on subclinical OCT 
-  * **BRAF inhibitors** predominantly cause uveitis rather than retinopathy* +  * **BRAF inhibitors** predominantly cause uveitis rather than retinopathy 
-  * **ERK inhibitors** produce MEKAR-like retinopathy with additional intraretinal edema, but events appear self-limited* +  * **ERK inhibitors** produce MEKAR-like retinopathy with additional intraretinal edema, but events appear self-limited 
-  * **KRAS inhibitors** have minimal ocular toxicity* +  * **KRAS inhibitors** have minimal ocular toxicity
- +
-===== 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. +
- +
-==== Step-by-Step Signal Transduction ==== +
- +
-  - **Extracellular stimulus → Receptor activation:** Growth factors bind to receptor tyrosine kinases (RTKs) such as EGFR, triggering receptor dimerization and autophosphorylation. +
-  - **Adaptor protein recruitment → RAS activation:** Phosphorylated RTKs recruit adaptor proteins (Shc, Grb2) and the guanine nucleotide exchange factor SOS, which converts RAS from inactive (RAS-GDP) to active (RAS-GTP). Three RAS isoforms exist: HRAS, KRAS, and NRAS. +
-  - **RAS → RAF (MAP3K tier):** Active RAS-GTP recruits RAF kinases (ARAF, BRAF, CRAF) to the plasma membrane for activation. BRAF is the most potent activator and the most frequently mutated in cancer (V600E). +
-  - **RAF → MEK (MAP2K tier):** Activated RAF phosphorylates MEK1/2. MEK is the only known physiological substrate of RAF. +
-  - **MEK → ERK (MAPK tier):** Activated MEK1/2 phosphorylate ERK1/2 at the conserved TEY motif. Both phosphorylation events are required for full activation. +
-  - **ERK → Downstream effectors:** ERK1/2 phosphorylate over 250 known substrates in the cytoplasm and nucleus, activating transcription factors (Elk-1, c-Fos, c-Myc, AP-1) that drive cell cycle progression. +
- +
-==== Key Regulatory Features ==== +
- +
-  * **Signal amplification:** Each tier amplifies the signal from upstream to downstream* +
-  * **Negative feedback:** ERK phosphorylates upstream components (SOS, RAF) to attenuate signaling* +
-  * **Scaffold proteins** (KSR1/2, IQGAP1, MP1) organize cascade components into signaling complexes* +
-  * **Crosstalk:** Cross-communication with the PI3K/AKT pathway and other MAPK cascades (JNK, p38)* +
- +
-==== Relevance to Cancer and Ocular Toxicity ==== +
- +
-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. +
- +
-===== What Does MAPK Stand For? ===== +
- +
-**MAPK** stands for **Mitogen-Activated Protein Kinase**. The name reflects the pathway's original discovery as a kinase cascade activated by mitogens — extracellular signals (such as growth factors) that stimulate cell division (mitosis). +
- +
- +
- +
-===== References ===== +
-### References With Hyperlinks – MAPK Pathway Drugs and Ocular Toxicity+
  
 ===== References ===== ===== References =====
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   - Lopez-Bergami P. The role of mitogen- and stress-activated protein kinase pathways in melanoma. //Pigment Cell Melanoma Res//. 2011.   - Lopez-Bergami P. The role of mitogen- and stress-activated protein kinase pathways in melanoma. //Pigment Cell Melanoma Res//. 2011.
   - Pyakurel A, Balmer D, Saba-El-Leil MK, et al. Loss of Extracellular Signal-Regulated Kinase 1/2 in the Retinal Pigment Epithelium Leads to RPE65 Decrease and Retinal Degeneration. //Mol Cell Biol//. 2017.   - Pyakurel A, Balmer D, Saba-El-Leil MK, et al. Loss of Extracellular Signal-Regulated Kinase 1/2 in the Retinal Pigment Epithelium Leads to RPE65 Decrease and Retinal Degeneration. //Mol Cell Biol//. 2017.
 +
 +{{tag>drugs}}