Enhanced apoptosis and tumor growth suppression elicited by combination of MEK (selumetinib) and mTOR kinase inhibitors (AZD8055).
Authors
Holt, Sarah VLogie, A
Davies, B
Alferez, D
Runswick, S
Fenton, S
Chresta, C
Gu, Y
Zhang, J
Wu, Y
Wilkinson, R
Guichard, S
Smith, P
Affiliation
Oncology iMed, AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom.Issue Date
2012-04-01
Metadata
Show full item recordAbstract
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.Citation
Enhanced apoptosis and tumor growth suppression elicited by combination of MEK (selumetinib) and mTOR kinase inhibitors (AZD8055). 2012, 72 (7):1804-13 Cancer ResJournal
Cancer ResearchDOI
10.1158/0008-5472.CAN-11-1780PubMed ID
22271687Type
ArticleLanguage
enISSN
1538-7445ae974a485f413a2113503eed53cd6c53
10.1158/0008-5472.CAN-11-1780
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