دورية أكاديمية
Combined targeting of MEK and PI3K/mTOR effector pathways is necessary to effectively inhibit NRAS mutant melanoma in vitro and in vivo.
| العنوان: | Combined targeting of MEK and PI3K/mTOR effector pathways is necessary to effectively inhibit NRAS mutant melanoma in vitro and in vivo. |
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| المؤلفون: | Posch C; Department of Dermatology, Mount Zion Cancer Research Center, San Francisco, CA 94115, USA. poschc@derm.ucsf.edu, Moslehi H, Feeney L, Green GA, Ebaee A, Feichtenschlager V, Chong K, Peng L, Dimon MT, Phillips T, Daud AI, McCalmont TH, LeBoit PE, Ortiz-Urda S |
| المصدر: | Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2013 Mar 05; Vol. 110 (10), pp. 4015-20. Date of Electronic Publication: 2013 Feb 19. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, DC : National Academy of Sciences |
| مواضيع طبية MeSH: | Phosphoinositide-3 Kinase Inhibitors*, GTP Phosphohydrolases/*genetics , MAP Kinase Signaling System/*drug effects , Melanoma/*drug therapy , Melanoma/*metabolism , Membrane Proteins/*genetics , TOR Serine-Threonine Kinases/*antagonists & inhibitors, Animals ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/pharmacology ; Apoptosis/drug effects ; Cell Line, Tumor ; Drug Synergism ; Female ; Humans ; Melanoma/genetics ; Melanoma/pathology ; Mice ; Mice, Nude ; Mutation ; Protein Kinase Inhibitors/administration & dosage ; Protein Kinase Inhibitors/pharmacology ; Signal Transduction/drug effects ; Xenograft Model Antitumor Assays |
| مستخلص: | Activating mutations in the neuroblastoma rat sarcoma viral oncogene homolog (NRAS) gene are common genetic events in malignant melanoma being found in 15-25% of cases. NRAS is thought to activate both mitogen activated protein kinase (MAPK) and PI3K signaling in melanoma cells. We studied the influence of different components on the MAP/extracellular signal-regulated (ERK) kinase (MEK) and PI3K/mammalian target of rapamycin (mTOR)-signaling cascade in NRAS mutant melanoma cells. In general, these cells were more sensitive to MEK inhibition compared with inhibition in the PI3K/mTOR cascade. Combined targeting of MEK and PI3K was superior to MEK and mTOR1,2 inhibition in all NRAS mutant melanoma cell lines tested, suggesting that PI3K signaling is more important for cell survival in NRAS mutant melanoma when MEK is inhibited. However, targeting of PI3K/mTOR1,2 in combination with MEK inhibitors is necessary to effectively abolish growth of NRAS mutant melanoma cells in vitro and regress xenografted NRAS mutant melanoma. Furthermore, we showed that MEK and PI3K/mTOR1,2 inhibition is synergistic. Expression analysis confirms that combined MEK and PI3K/mTOR1,2 inhibition predominantly influences genes in the rat sarcoma (RAS) pathway and growth factor receptor pathways, which signal through MEK/ERK and PI3K/mTOR, respectively. Our results suggest that combined targeting of the MEK/ERK and PI3K/mTOR pathways has antitumor activity and might serve as a therapeutic option in the treatment of NRAS mutant melanoma, for which there are currently no effective therapies. |
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| معلومات مُعتمدة: | K08 CA155035 United States CA NCI NIH HHS; 1K08CA155035-01A1 United States CA NCI NIH HHS |
| المشرفين على المادة: | 0 (Antineoplastic Agents) 0 (Membrane Proteins) 0 (Phosphoinositide-3 Kinase Inhibitors) 0 (Protein Kinase Inhibitors) EC 2.7.1.1 (MTOR protein, human) EC 2.7.11.1 (TOR Serine-Threonine Kinases) EC 3.6.1.- (GTP Phosphohydrolases) EC 3.6.1.- (NRAS protein, human) |
| تواريخ الأحداث: | Date Created: 20130223 Date Completed: 20130502 Latest Revision: 20220311 |
| رمز التحديث: | 20221213 |
| مُعرف محوري في PubMed: | PMC3593920 |
| DOI: | 10.1073/pnas.1216013110 |
| PMID: | 23431193 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1091-6490 |
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| DOI: | 10.1073/pnas.1216013110 |