MAPK Pathway Drugs and Ocular Toxicity -CEW

This page is read only. You can view the source, but not change it. Ask your administrator if you think this is wrong.
====== 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).

===== 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]]

==== 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.


===== Drugs in the MAPK/RAS-RAF-MEK-ERK Pathway With Ocular Toxicity =====

==== BRAF Inhibitors (Type I) ====

^ Drug (Brand Name) ^ Primary Ocular Toxicities ^ Key Details ^
| **Vemurafenib** (Zelboraf) | Uveitis (anterior uveitis, panuveitis), photosensitivity | Uveitis in ~4% of patients; highest ocular signal among BRAF inhibitors |
| **Dabrafenib** (Tafinlar) | Uveitis | Lower incidence (~1%); favorable ocular profile in pediatric cohorts |
| **Encorafenib** (Braftovi) | Uveitis (when combined with binimetinib) | 4% uveitis incidence in COLUMBUS trial |

==== MEK Inhibitors ====

^ Drug (Brand Name) ^ Primary Ocular Toxicities ^ Key Details ^
| **Trametinib** (Mekinist) | RPED, serous retinal detachment, chorioretinopathy, RVO | FDA label warns of RPED and RVO |
| **Cobimetinib** (Cotellic) | Serous retinopathy (MEKAR), blurred vision | 17.9% serous retinopathy in integrated analysis; median onset 15 days |
| **Binimetinib** (Mektovi) | Serous retinopathy, RVO, uveitis | FDA label mandates visual symptom assessment at each visit |
| **Selumetinib** (Koselugo) | MEKAR, blurred vision | FDA-approved for pediatric [NF1](https://www.openevidence.com/rare-disease/neurofibromatosis-type-1); ~1.4% central serous retinopathy |

==== Pan-RAF Inhibitors ====

^ Drug (Brand Name) ^ Primary Ocular Toxicities ^ Key Details ^
| **Tovorafenib** (Ojemda) | MEKAR, photosensitivity, periorbital edema | Pan-RAF inhibitor; ocular profile overlaps with MEK inhibitors |
| **Naporafenib** (investigational) | Expected class-related retinopathy | Being studied in combination with trametinib |
| **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 |

=== 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 ====

^ Drug (Brand Name) ^ Primary Ocular Toxicities ^ Key Details ^
| **Ulixertinib/BVD-523** (investigational) | Subretinal fluid (MEKAR-like), intraretinal edema | 100% bilateral, 95% foveal involvement; all cases reversible |
| **ATG-017** (investigational) | Retinopathy (grade 3 DLT), blurred vision | Dose-limiting ocular toxicity at higher doses |
| **LY3214996** (investigational) | Expected class-related retinopathy | Preclinical data show ERK loss in RPE leads to retinal degeneration |

==== KRAS Inhibitors ====

^ Drug (Brand Name) ^ Primary Ocular Toxicities ^ Key Details ^
| **Sotorasib** (Lumakras) | Conjunctivitis (11% in mCRC combination arm) | Minimal retinal toxicity; no MEKAR-type events |
| **Adagrasib** (Krazati) | No significant ocular toxicity reported | Primary toxicities are GI and hepatic |

==== 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
  * **BRAF inhibitors** predominantly cause uveitis rather than retinopathy
  * **ERK inhibitors** produce MEKAR-like retinopathy with additional intraretinal edema, but events appear self-limited
  * **KRAS inhibitors** have minimal ocular toxicity

===== 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. [[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. [[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.
  - Huang S, Zhang Y, Shu H, et al. Advances of the MAPK pathway in the treatment of spinal cord injury. //CNS Neurosci Ther//. 2024.
  - Fang JY, Richardson BC. The MAPK Signalling Pathways and Colorectal Cancer. //Lancet Oncol//. 2005.
  - Terrell EM, Morrison DK. Ras-Mediated Activation of the Raf Family Kinases. //Cold Spring Harb Perspect Med//. 2019.
  - 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.

{{tag>drugs}}
drugs