التفاصيل البيبلوغرافية
| العنوان: |
COMBINING SOS1 AND MEK INHIBITORS IN A MURINE MODEL OF PLEXIFORM NEUROFIBROMA RESULTS IN TUMOR SHRINKAGE |
| المؤلفون: |
Jackson, Mark, Ahmari, Niousha, Wu, Jianqiang, Rizvi, Tilat A, Fugate, Elizabeth, Kim, Mi-Ok, Dombi, Eva, Arnhof, Heribert, Boehmelt, Guido, Düchs, Matthias J, Long, Clive J, Maier, Udo, Trapani, Francesca, Hofmann, Marco H, Ratner, Nancy |
| المصدر: |
Journal of Pharmacology and Experimental Therapeutics, vol 385, iss 2 |
| بيانات النشر: |
eScholarship, University of California |
| سنة النشر: |
2023 |
| المجموعة: |
University of California: eScholarship |
| مصطلحات موضوعية: |
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Rare Diseases, Neurosciences, Cancer, Neurofibromatosis, Pediatric, Animals, Mice, Disease Models, Animal, Extracellular Signal-Regulated MAP Kinases, Mitogen-Activated Protein Kinase Kinases, Neurofibroma, Plexiform, Neurofibromatosis 1, Protein Kinase Inhibitors, Proto-Oncogene Proteins p21(ras), Tumor Microenvironment, SOS1 Protein, Pharmacology and Pharmaceutical Sciences, Pharmacology & Pharmacy |
| جغرافية الموضوع: |
jpet-ar-2022-001431 |
| الوصف: |
Individuals with neurofibromatosis type 1 develop rat sarcoma virus (RAS)-mitogen-activated protein kinase-mitogen-activated and extracellular signal-regulated kinase (RAS-MAPK-MEK)-driven nerve tumors called neurofibromas. Although MEK inhibitors transiently reduce volumes of most plexiform neurofibromas in mouse models and in neurofibromatosis type 1 (NF1) patients, therapies that increase the efficacy of MEK inhibitors are needed. BI-3406 is a small molecule that prevents Son of Sevenless (SOS)1 interaction with Kirsten rat sarcoma viral oncoprotein (KRAS)-GDP, interfering with the RAS-MAPK cascade upstream of MEK. Single agent SOS1 inhibition had no significant effect in the DhhCre;Nf1 fl/fl mouse model of plexiform neurofibroma, but pharmacokinetics (PK)-driven combination of selumetinib with BI-3406 significantly improved tumor parameters. Tumor volumes and neurofibroma cell proliferation, reduced by MEK inhibition, were further reduced by the combination. Neurofibromas are rich in ionized calcium binding adaptor molecule 1 (Iba1)+ macrophages; combination treatment resulted in small and round macrophages, with altered cytokine expression indicative of altered activation. The significant effects of MEK inhibitor plus SOS1 inhibition in this preclinical study suggest potential clinical benefit of dual targeting of the RAS-MAPK pathway in neurofibromas. SIGNIFICANCE STATEMENT: Interfering with the RAS-mitogen-activated protein kinase (RAS-MAPK) cascade upstream of mitogen activated protein kinase kinase (MEK), together with MEK inhibition, augment effects of MEK inhibition on neurofibroma volume and tumor macrophages in a preclinical model system. This study emphasizes the critical role of the RAS-MAPK pathway in controlling tumor cell proliferation and the tumor microenvironment in benign neurofibromas. |
| نوع الوثيقة: |
article in journal/newspaper |
| وصف الملف: |
application/pdf |
| اللغة: |
unknown |
| العلاقة: |
qt29w8z392; https://escholarship.org/uc/item/29w8z392Test |
| الإتاحة: |
https://escholarship.org/uc/item/29w8z392Test |
| حقوق: |
public |
| رقم الانضمام: |
edsbas.BB6FDB57 |
| قاعدة البيانات: |
BASE |
