Enhanced Apoptosis and Tumor Growth Suppression Elicited by Combination of MEK (Selumetinib) and mTOR Kinase Inhibitors (AZD8055)
| Autor: | Sylvie Guichard, Robert W. Wilkinson, Sarah L. Fenton, Yi-Long Wu, Paul D. Smith, Jingchuan Zhang, Barry R. Davies, Armelle Logie, Sarah V. Holt, Sarah Runswick, D Alferez, Yi Gu, Christine M. Chresta |
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| Rok vydání: | 2012 |
| Předmět: |
MAPK/ERK pathway
Cancer Research Lung Neoplasms MAP Kinase Signaling System Morpholines Apoptosis mTORC1 Mitogen-activated protein kinase kinase Biology mTORC2 Proto-Oncogene Proteins p21(ras) Mice Carcinoma Non-Small-Cell Lung Proto-Oncogene Proteins Animals Humans Protein Kinase Inhibitors Protein kinase B PI3K/AKT/mTOR pathway Mitogen-Activated Protein Kinase Kinases Gene Expression Profiling TOR Serine-Threonine Kinases RPTOR Neoplasms Experimental Xenograft Model Antitumor Assays Oncology Mutation ras Proteins Cancer research Selumetinib Benzimidazoles Female Colorectal Neoplasms Signal Transduction |
| Zdroj: | Cancer Research. 72:1804-1813 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-11-1780 |
| Popis: | The mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase/AKT signaling pathways interact at multiple nodes in cancer, including at mTOR complexes, suggesting an increased likelihood of redundancy and innate resistance to any therapeutic effects of single pathway inhibition. In this study, we investigated the therapeutic effects of combining the MAPK extracellular signal–regulated kinase (MEK)1/2 inhibitor selumetinib (AZD6244) with the dual mTORC1 and mTORC2 inhibitor (AZD8055). Concurrent dosing in nude mouse xenograft models of human lung adenocarcinoma (non–small cell lung cancers) and colorectal carcinoma was well tolerated and produced increased antitumor efficacy relative to the respective monotherapies. Pharmacodynamic analysis documented reciprocal pathway inhibition associated with increased apoptosis and Bim expression in tumor tissue from the combination group, where key genes such as DUSP6 that are under MEK functional control were also modulated. Our work offers a strong rationale to combine selumetinib and AZD8055 in clinical trials as an attractive therapeutic strategy. Cancer Res; 72(7); 1804–13. ©2012 AACR. |
| Databáze: | OpenAIRE |
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