دورية أكاديمية
Titration of signalling output: insights into clinical combinations of MEK and AKT inhibitors.
| العنوان: | Titration of signalling output: insights into clinical combinations of MEK and AKT inhibitors. |
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| المؤلفون: | Stewart, A, Thavasu, P, de Bono, JS, Banerji, U |
| المساهمون: | De Bono, Johann, Banerji, Udai |
| بيانات النشر: | OXFORD UNIV PRESS |
| سنة النشر: | 2016 |
| المجموعة: | The Institute of Cancer Research (ICR): Publications Repository |
| مصطلحات موضوعية: | Tumor Cells, Cultured, Humans, Neoplasms, Benzamides, Diphenylamine, Proto-Oncogene Proteins B-raf, MAP Kinase Kinase 1, Protein Kinase Inhibitors, Enzyme-Linked Immunosorbent Assay, Signal Transduction, Cell Proliferation, Drug Synergism, Mutation, Proto-Oncogene Proteins p21(ras), Proto-Oncogene Proteins c-akt, Phosphatidylinositol 3-Kinases, Class I Phosphatidylinositol 3-Kinases |
| الوصف: | BACKGROUND: We aimed to understand the relative contributions of inhibiting MEK and AKT on cell growth to guide combinations of these agents. MATERIALS AND METHODS: A panel of 20 cell lines was exposed to either the MEK inhibitor, PD0325901, or AKT inhibitor, AKT 1/2 inhibitor. p-ERK and p-S6 ELISAs were used to define degrees of MEK and AKT inhibition, respectively. Growth inhibition to different degrees of MEK and AKT inhibition, either singly or in combination using 96-h sulphorhodamine assays was then studied. RESULTS: A significantly greater growth inhibition was seen in BRAF(M) and PIK3CA(M) cells upon maximal MEK (P = 0.004) and AKT inhibition (P = 0.038), respectively. KRAS(M) and BRAF/PIK3CA/KRAS(WT) cells were not significantly more likely to be sensitive to MEK or AKT inhibition. Significant incremental growth inhibition of the combination of MEK + AKT over either MEK or AKT inhibition alone was seen when MEK + AKT was inhibited maximally and not when sub-maximal inhibition of both MEK + AKT was used (11/20 cell lines versus 1/20 cell lines; P = 0.0012). CONCLUSIONS: KRAS(M) cells are likely to benefit from combinations of MEK and AKT inhibitors. Sub-maximally inhibiting both MEK and AKT within a combination, in a majority of instances, does not significantly increase growth inhibition compared with maximally inhibiting MEK or AKT alone and alternative phase I trial designs are needed to clinically evaluate such combinations. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | Print-Electronic; 1510; application/pdf |
| اللغة: | English |
| تدمد: | 0923-7534 1569-8041 |
| العلاقة: | Annals of oncology : official journal of the European Society for Medical Oncology, 2015, 26 (7), pp. 1504 - 1510; https://repository.icr.ac.uk/handle/internal/263Test |
| DOI: | 10.1093/annonc/mdv188 |
| الإتاحة: | https://doi.org/10.1093/annonc/mdv188Test https://repository.icr.ac.uk/handle/internal/263Test |
| حقوق: | https://creativecommons.org/licenses/by-nc/4.0Test |
| رقم الانضمام: | edsbas.8D98678F |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 09237534 15698041 |
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| DOI: | 10.1093/annonc/mdv188 |