Targeting TBK1 Inhibits Migration and Resistance to MEK Inhibitors in Mutant NRAS Melanoma
| العنوان: | Targeting TBK1 Inhibits Migration and Resistance to MEK Inhibitors in Mutant NRAS Melanoma |
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| المؤلفون: | Ha Linh Vu, Andrew E. Aplin |
| المصدر: | Molecular Cancer Research. 12:1509-1519 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2014. |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | Neuroblastoma RAS viral oncogene homolog, Cancer Research, Skin Neoplasms, Apoptosis, Thiophenes, IκB kinase, Protein Serine-Threonine Kinases, Biology, Mitogen-activated protein kinase kinase, Article, GTP Phosphohydrolases, TANK-binding kinase 1, Cell Movement, Cell Line, Tumor, medicine, Humans, Neoplasm Invasiveness, Molecular Targeted Therapy, Melanoma, Protein Kinase Inhibitors, Molecular Biology, PI3K/AKT/mTOR pathway, Mitogen-Activated Protein Kinase Kinases, Kinase, Membrane Proteins, medicine.disease, Pyrimidines, Oncology, Drug Resistance, Neoplasm, Gene Knockdown Techniques, Mutation, Cancer research, Benzimidazoles, ARAF |
| الوصف: | Melanoma is a devastating form of skin cancer with limited therapeutic options. Fifteen to 20% of patients with melanoma have an activating mutation in the GTPase, NRAS. The major downstream effectors of RAS are RAFs (ARAF, BRAF, and CRAF), phosphoinositide 3-kinase (PI3K), and the Ral guanine exchange factors (RalGEF). TANK-binding kinase 1 (TBK1) is an atypical IκB kinase family member that acts downstream of RalGEFs. Whereas many studies have analyzed RAF and PI3K signaling in mutant NRAS melanoma, the role of RalGEF/Ral is understudied and TBK1 has not been examined. To address this, TBK1 was modulated with knockdown approaches and targeted therapies to determine the role of TBK1 in motility, apoptosis, and signaling. In melanoma, NRAS overexpression increased TBK1 phosphorylation. TBK1 depletion inhibited migration and invasion, whereas its constitutive overexpression led to an increase in invasion. In three-dimensional systems that mimic the dermal microenvironment, TBK1 depletion or inhibition cooperated with MEK inhibitors to promote apoptosis, particularly in the context of MEK-insensitive mutant NRAS. This effect was absent in melanoma cells that are wild-type for NRAS. These results suggest the utility of TBK1 inhibitors as part of a treatment regimen for patients with mutant NRAS melanoma, for whom there are no current effective therapies. Implications: TBK1 promotes the malignant properties of NRAS-mutant melanoma and its targeting, in combination with MEK, promotes apoptosis, thus providing a potential novel targeted therapeutic option. Mol Cancer Res; 12(10); 1509–19. ©2014 AACR. |
| تدمد: | 1557-3125 1541-7786 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5a5e2316c27d7cfe2ed70ce2abdfdb94 https://doi.org/10.1158/1541-7786.mcr-14-0204 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....5a5e2316c27d7cfe2ed70ce2abdfdb94 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15573125 15417786 |
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