Targeting RAS/MAPK Signaling: MEK Inhibitors as Breakthrough Therapy for NF1-Associated Plexiform Neurofibroma- A Review
Fuente:
Zenodo
Guardado en:
| Autores principales: | , , , , , , , , , |
|---|---|
| Formato: | Recurso digital |
| Lenguaje: | inglés |
| Publicado: |
Zenodo
2025
|
| Materias: | |
| Acceso en línea: | |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| _version_ | 1866901611972919296 |
|---|---|
| author | Martyna Nowak Daria Podleśna Nicola Stencel Gabriela Majta Mateusz Witowicz Konrad Krupa Katarzyna Kilarowska Aleksandra Machnik Aleksander Tuleja Jakub Rudzki |
| author_facet | Martyna Nowak Daria Podleśna Nicola Stencel Gabriela Majta Mateusz Witowicz Konrad Krupa Katarzyna Kilarowska Aleksandra Machnik Aleksander Tuleja Jakub Rudzki |
| contents | <p><strong><span lang="EN-US">Abstract— </span></strong><span lang="EN-US">Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder resulting from NF1 gene mutations that cause constitutive activation of the RAS/MAPK signaling pathway. This dysregulation promotes the development of plexiform neurofibromas (PNs), benign tumors associated with notable morbidity when inoperable. This review<span> </span>summarizes<span> </span>advances<span> </span>in<span> </span>novel targeted therapies of NF1-associated PNs,<span> </span>focusing<span> </span>on<span> </span>MEK<span> </span>inhibitors<span> </span>with<span> </span>emphasis<span> </span>on<span> </span>selumetinib<span> </span>and<span> </span>mirdametinib.<span> </span>A<span> </span>systematic literature search was performed using PubMed, ResearchGate, and Google Scholar for studies published up to July 2025, complemented by manual reference<span> </span>screening.<span> </span>MEKis<span> </span>suppress<span> </span>MEK1/2<span> </span>activity,<span> </span>thereby<span> </span>attenuating<span> </span>aberrant<span> </span>RAS/MAPK<span> </span>signaling and<span> </span>tumor<span> </span>growth.<span> </span>Selumetinib,<span> </span>approved<span> </span>by<span> </span>the<span> </span>U.S.<span> </span>Food<span> </span>and<span> </span>Drug<span> </span>Administration<span> </span>(FDA)<span> </span>in<span> </span>2020<span> </span>for<span> </span>pediatric<span> </span>NF1-PNs,<span> </span>achieved a ≥20% tumor volume reduction in 74% of patients and yielded significant improvements in pain<span> </span>and<span> </span>quality<span> </span>of<span> </span>life.<span> </span>Mirdametinib, approved in 2025 for both pediatric<span> </span>and<span> </span>adult<span> </span>populations,<span> </span>demonstrated<span> </span>a<span> </span>median<span> </span>41%<span> </span>tumor<span> </span>reduction<span> </span>and<span> </span>sustained<span> </span>symptomatic benefit. The principal toxicities included dermatologic, gastrointestinal, ocular, and cardiac events, generally manageable with dose adjustment and monitoring. Despite substantial clinical benefit, unresolved challenges include long-term safety, optimal dosing,<span> </span>and the integration of MEK inhibition with surgical and multimodal approaches.<span> </span>Future<span> </span>research<span> </span>should<span> </span>focus<span> </span>on<span> </span>combination<span> </span>therapies and<span> </span>refinement<span> </span>of<span> </span>individualized<span> </span>treatment<span> </span>strategies.<span> </span>MEK<span> </span>inhibitors<span> </span>represent<span> </span>a<span> </span>major<span> </span>therapeutic<span> </span>breakthrough<span> </span>for NF1-associated PNs, offering durable tumor control, functional improvement, and new opportunities for precision medicine in neurofibromatosis care.</span></p> <p><strong><span lang="EN-US"> </span></strong></p> <p><strong><span lang="EN-US">Keywords</span></strong><span lang="EN-US">—<span> </span>neurofibromatosis,<span> </span>neurofibromatosis<span> </span>type<span> </span>1,<span> </span>NF1,<span> </span>plexiform<span> </span>neurofibroma,<span> </span>MEK<span> </span>inhibitors;<span> </span>targeted<span> </span>therapy,<span> </span>selumetinib,<span> </span><span>mirdametinib</span></span></p> |
| format | Recurso digital |
| id | zenodo_https___doi_org_10_5281_zenodo_17746451 |
| institution | Zenodo |
| language | eng |
| publishDate | 2025 |
| publisher | Zenodo |
| record_format | zenodo |
| spellingShingle | Targeting RAS/MAPK Signaling: MEK Inhibitors as Breakthrough Therapy for NF1-Associated Plexiform Neurofibroma- A Review Martyna Nowak Daria Podleśna Nicola Stencel Gabriela Majta Mateusz Witowicz Konrad Krupa Katarzyna Kilarowska Aleksandra Machnik Aleksander Tuleja Jakub Rudzki neurofibromatosis, neurofibromatosis type 1, NF1, plexiform neurofibroma, MEK inhibitors; targeted therapy, selumetinib, mirdametinib <p><strong><span lang="EN-US">Abstract— </span></strong><span lang="EN-US">Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder resulting from NF1 gene mutations that cause constitutive activation of the RAS/MAPK signaling pathway. This dysregulation promotes the development of plexiform neurofibromas (PNs), benign tumors associated with notable morbidity when inoperable. This review<span> </span>summarizes<span> </span>advances<span> </span>in<span> </span>novel targeted therapies of NF1-associated PNs,<span> </span>focusing<span> </span>on<span> </span>MEK<span> </span>inhibitors<span> </span>with<span> </span>emphasis<span> </span>on<span> </span>selumetinib<span> </span>and<span> </span>mirdametinib.<span> </span>A<span> </span>systematic literature search was performed using PubMed, ResearchGate, and Google Scholar for studies published up to July 2025, complemented by manual reference<span> </span>screening.<span> </span>MEKis<span> </span>suppress<span> </span>MEK1/2<span> </span>activity,<span> </span>thereby<span> </span>attenuating<span> </span>aberrant<span> </span>RAS/MAPK<span> </span>signaling and<span> </span>tumor<span> </span>growth.<span> </span>Selumetinib,<span> </span>approved<span> </span>by<span> </span>the<span> </span>U.S.<span> </span>Food<span> </span>and<span> </span>Drug<span> </span>Administration<span> </span>(FDA)<span> </span>in<span> </span>2020<span> </span>for<span> </span>pediatric<span> </span>NF1-PNs,<span> </span>achieved a ≥20% tumor volume reduction in 74% of patients and yielded significant improvements in pain<span> </span>and<span> </span>quality<span> </span>of<span> </span>life.<span> </span>Mirdametinib, approved in 2025 for both pediatric<span> </span>and<span> </span>adult<span> </span>populations,<span> </span>demonstrated<span> </span>a<span> </span>median<span> </span>41%<span> </span>tumor<span> </span>reduction<span> </span>and<span> </span>sustained<span> </span>symptomatic benefit. The principal toxicities included dermatologic, gastrointestinal, ocular, and cardiac events, generally manageable with dose adjustment and monitoring. Despite substantial clinical benefit, unresolved challenges include long-term safety, optimal dosing,<span> </span>and the integration of MEK inhibition with surgical and multimodal approaches.<span> </span>Future<span> </span>research<span> </span>should<span> </span>focus<span> </span>on<span> </span>combination<span> </span>therapies and<span> </span>refinement<span> </span>of<span> </span>individualized<span> </span>treatment<span> </span>strategies.<span> </span>MEK<span> </span>inhibitors<span> </span>represent<span> </span>a<span> </span>major<span> </span>therapeutic<span> </span>breakthrough<span> </span>for NF1-associated PNs, offering durable tumor control, functional improvement, and new opportunities for precision medicine in neurofibromatosis care.</span></p> <p><strong><span lang="EN-US"> </span></strong></p> <p><strong><span lang="EN-US">Keywords</span></strong><span lang="EN-US">—<span> </span>neurofibromatosis,<span> </span>neurofibromatosis<span> </span>type<span> </span>1,<span> </span>NF1,<span> </span>plexiform<span> </span>neurofibroma,<span> </span>MEK<span> </span>inhibitors;<span> </span>targeted<span> </span>therapy,<span> </span>selumetinib,<span> </span><span>mirdametinib</span></span></p> |
| title | Targeting RAS/MAPK Signaling: MEK Inhibitors as Breakthrough Therapy for NF1-Associated Plexiform Neurofibroma- A Review |
| topic | neurofibromatosis, neurofibromatosis type 1, NF1, plexiform neurofibroma, MEK inhibitors; targeted therapy, selumetinib, mirdametinib |
| url | https://doi.org/10.5281/zenodo.17746451 |