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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 =====
Line 36: Line 51:
 | **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 ====
Line 52: Line 78:
 ==== 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 – MAPK Pathway Drugs and Ocular Toxicity+
  
 ===== References ===== ===== References =====
  
-  - Ullah R, Yin Q, Snell AH, Wan L. RAF-MEK-ERK Pathway in Cancer Evolution and Treatment. //Semin Cancer Biol//. 2022;85:123-154. PMID: 33992782. +  - Ullah R, Yin Q, Snell AH, Wan L. RAF-MEK-ERK Pathway in Cancer Evolution and Treatment. //Semin Cancer Biol//. 2022;85:123-154. [[https://pubmed.ncbi.nlm.nih.gov/33992782/|PMID: 33992782]] 
-  - Barbosa R, Acevedo LA, Marmorstein R. The MEK/ERK Network as a Therapeutic Target in Human Cancer. //Mol Cancer Res//. 2021;19(3):361-374. PMID: 33139506.+  - Barbosa R, Acevedo LA, Marmorstein R. The MEK/ERK Network as a Therapeutic Target in Human Cancer. //Mol Cancer Res//. 2021;19(3):361-374. [[https://pubmed.ncbi.nlm.nih.gov/33139506/|PMID: 33139506]] 
 +  - Roberts PJ, Der CJ. Targeting the Raf-Mek-Erk Mitogen-Activated Protein Kinase Cascade for the Treatment of Cancer. //Oncogene//. 2007;26(22):3291-3310. [[https://pubmed.ncbi.nlm.nih.gov/17496923/|PMID: 17496923]] 
 +  - Roskoski R. ERK1/2 MAP Kinases: Structure, Function, and Regulation. //Pharmacol Res//. 2012;66(2):105-143. [[https://pubmed.ncbi.nlm.nih.gov/22569528/|PMID: 22569528]] 
 +  - Food and Drug Administration. MEKTOVI (binimetinib) prescribing information. 2025. [[https://www.accessdata.fda.gov/drugsatfda*docs/label/2023/210498s006lbl.pdf|FDA Label]]* 
 +  - Food and Drug Administration. Mekinist (trametinib) prescribing information. 2026. [[https://www.accessdata.fda.gov/drugsatfda*docs/label/2024/204114s024lbl.pdf|FDA Label]]* 
 +  - Food and Drug Administration. LUMAKRAS (sotorasib) prescribing information. 2025. [[https://www.accessdata.fda.gov/drugsatfda*docs/label/2023/214665s003lbl.pdf|FDA Label]]* 
 +  - Mettler C, Monnet D, Kramkimel N, et al. Ocular Safety Profile of BRAF and MEK Inhibitors: Data From the World Health Organization Pharmacovigilance Database. //Ophthalmology//. 2021;128(12):1748-1757. [[https://pubmed.ncbi.nlm.nih.gov/34000304/|PMID: 34000304]] 
 +  - Huang S, Guo Z, Wang M, et al. Ocular Adverse Events Associated With BRAF and MEK Inhibitor Combination Therapy: A Pharmacovigilance Disproportionality Analysis of the FDA Adverse Event Reporting System. //Expert Opin Drug Saf//. 2023. [[https://pubmed.ncbi.nlm.nih.gov/36896641/|PMID: 36896641]] 
 +  - Zhang Z, Wu Q, Wang Y, et al. Adverse Events Associated With Dabrafenib, Trametinib, and Their Combination Therapy: A Disproportionality Analysis of the FDA Adverse Event Reporting System (FAERS) Database. //Pharmacoepidemiol Drug Saf//. 2025. 
 +  - Barteselli G, Goodman GR, Patel Y, et al. Characterization of Serous Retinopathy Associated With Cobimetinib: Integrated Safety Analysis of Four Studies. //Drug Saf//. 2022;45(12):1541-1555. [[https://pubmed.ncbi.nlm.nih.gov/36310331/|PMID: 36310331]] 
 +  - Guo C, Chénard-Poirier M, Roda D, et al. Intermittent Schedules of the Oral RAF-MEK Inhibitor CH5126766/VS-6766 in Patients With RAS/RAF-mutant Solid Tumours and Multiple Myeloma: A Single-Centre, Open-Label, Phase 1 Dose-Escalation and Basket Dose-Expansion Study. //Lancet Oncol//. 2020;21(11):1478-1488. [[https://doi.org/10.1016/S1470-2045(20)30464-2|DOI]] 
 +  - Francis JH, Canestraro J, Haggag-Lindgren D, et al. Clinical and Morphologic Characteristics of Extracellular Signal-Regulated Kinase Inhibitor-Associated Retinopathy. //Ophthalmol Retina//. 2021;5(12):1200-1215. [[https://pubmed.ncbi.nlm.nih.gov/34102344/|PMID: 34102344]] 
 +  - Sullivan RJ, Infante JR, Janku F, et al. First-in-Class ERK1/2 Inhibitor Ulixertinib (BVD-523) in Patients With MAPK Mutant Advanced Solid Tumors: Results of a Phase I Dose-Escalation and Expansion Study. //Cancer Discov//. 2018;8(2):184-195. [[https://pubmed.ncbi.nlm.nih.gov/29247021/|PMID: 29247021]] 
 +  - Wahlroos S, Teng C, Tran B, et al. Results of a first-in-human, dose-escalation phase 1 study of the ERK1/2 inhibitor ATG-017 in patients with advanced solid tumors. 2024 ASCO Annual Meeting. [[https://clinicaltrials.gov/ct2/show/NCT04305249|ClinicalTrials.gov: NCT04305249]] 
 +  - Sammons RM, Ghose R, Tsai KY, Dalby KN. Targeting ERK beyond the boundaries of the kinase active site in melanoma. //Mol Carcinog//. 2019;58(9):1551-1570. [[https://pubmed.ncbi.nlm.nih.gov/31148235/|PMID: 31148235]]
   - Shang J, Lu S, Jiang Y, Zhang J. Allosteric modulators of MEK1: drug design and discovery. //Chem Biol Drug Des//. 2016.   - Shang J, Lu S, Jiang Y, Zhang J. Allosteric modulators of MEK1: drug design and discovery. //Chem Biol Drug Des//. 2016.
   - Huang S, Zhang Y, Shu H, et al. Advances of the MAPK pathway in the treatment of spinal cord injury. //CNS Neurosci Ther//. 2024.   - Huang S, Zhang Y, Shu H, et al. Advances of the MAPK pathway in the treatment of spinal cord injury. //CNS Neurosci Ther//. 2024.
-  - Sammons RM, Ghose R, Tsai KY, Dalby KN. Targeting ERK beyond the boundaries of the kinase active site in melanoma. //Mol Carcinog//. 2019;58(9):1551-1570. 
-  - Roberts PJ, Der CJ. Targeting the Raf-Mek-Erk Mitogen-Activated Protein Kinase Cascade for the Treatment of Cancer. //Oncogene//. 2007;26(22):3291-3310. PMID: 17496923. 
   - Fang JY, Richardson BC. The MAPK Signalling Pathways and Colorectal Cancer. //Lancet Oncol//. 2005.   - Fang JY, Richardson BC. The MAPK Signalling Pathways and Colorectal Cancer. //Lancet Oncol//. 2005.
-  - Jeon H, Tkacik E, Eck MJ. Signaling From RAS to RAF: The Molecules and Their Mechanisms. //Annu Rev Biochem//. 2024. 
   - Terrell EM, Morrison DK. Ras-Mediated Activation of the Raf Family Kinases. //Cold Spring Harb Perspect Med//. 2019.   - Terrell EM, Morrison DK. Ras-Mediated Activation of the Raf Family Kinases. //Cold Spring Harb Perspect Med//. 2019.
-  - Roskoski R. ERK1/2 MAP Kinases: Structure, Function, and Regulation. //Pharmacol Res//. 2012;66(2):105-143. PMID: 22569528. 
   - 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.
-  - Food and Drug Administration. MEKTOVI (binimetinib) prescribing information. 2025. + 
-  - Food and Drug Administration. Mekinist (trametinib) prescribing information. 2026. +{{tag>drugs}}
-  - Food and Drug Administration. LUMAKRAS (sotorasib) prescribing information. 2025. +
-  - Mettler C, Monnet D, Kramkimel N, et al. Ocular Safety Profile of BRAF and MEK Inhibitors: Data From the World Health Organization Pharmacovigilance Database. //Ophthalmology//. 2021;128(12):1748-1757. PMID: 34000304. +
-  - Huang S, Guo Z, Wang M, et al. Ocular Adverse Events Associated With BRAF and MEK Inhibitor Combination Therapy: A Pharmacovigilance Disproportionality Analysis of the FDA Adverse Event Reporting System. //Expert Opin Drug Saf//. 2023. PMID: 36896641. +
-  - Zhang Z, Wu Q, Wang Y, et al. Adverse Events Associated With Dabrafenib, Trametinib, and Their Combination Therapy: A Disproportionality Analysis of the FDA Adverse Event Reporting System (FAERS) Database. //Pharmacoepidemiol Drug Saf//. 2025. +
-  - Barteselli G, Goodman GR, Patel Y, et al. Characterization of Serous Retinopathy Associated With Cobimetinib: Integrated Safety Analysis of Four Studies. //Drug Saf//. 2022;45(12):1541-1555. PMID: 36310331. +
-  - Guo C, Chénard-Poirier M, Roda D, et al. Intermittent Schedules of the Oral RAF-MEK Inhibitor CH5126766/VS-6766 in Patients With RAS/RAF-mutant Solid Tumours and Multiple Myeloma: A Single-Centre, Open-Label, Phase 1 Dose-Escalation and Basket Dose-Expansion Study. //Lancet Oncol//. 2020;21(11):1478-1488. +
-  - Francis JH, Canestraro J, Haggag-Lindgren D, et al. Clinical and Morphologic Characteristics of Extracellular Signal-Regulated Kinase Inhibitor-Associated Retinopathy. //Ophthalmol Retina//. 2021;5(12):1200-1215. PMID: 34102344. +
-  - Sullivan RJ, Infante JR, Janku F, et al. First-in-Class ERK1/2 Inhibitor Ulixertinib (BVD-523) in Patients With MAPK Mutant Advanced Solid Tumors: Results of a Phase I Dose-Escalation and Expansion Study. //Cancer Discov//. 2018;8(2):184-195. PMID: 29247021. +
-  - Wahlroos S, Teng C, Tran B, et al. Results of a first-in-human, dose-escalation phase 1 study of the ERK1/2 inhibitor ATG-017 in patients with advanced solid tumors. 2024.+