Enhanced Apoptosis and Tumor Growth Suppression Elicited by Combination of MEK (Selumetinib) and mTOR Kinase Inhibitors (AZD8055)

• Published in: Cancer research (Chicago, Ill.) Ill.), 2012-04, Vol.72 (7), p.1804-1813
• Main Authors: HOLT, Sarah V, LOGIE, Armelle, WILKINSON, Robert W, GUICHARD, Sylvie M, SMITH, Paul D, DAVIES, Barry R, ALFEREZ, Denis, RUNSWICK, Sarah, FENTON, Sarah, CHRESTA, Christine M, YI GU, JINGCHUAN ZHANG, WU, Yi-Long
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Apoptosis - drug effects; Benzimidazoles - administration & dosage; Biological and medical sciences; Carcinoma, Non-Small-Cell Lung - drug therapy; Colorectal Neoplasms - drug therapy; Female; Gene Expression Profiling; Humans; Lung Neoplasms - drug therapy; MAP Kinase Signaling System - physiology; Medical sciences; Mice; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; Morpholines - administration & dosage; Mutation; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - pathology; Pharmacology. Drug treatments; Protein Kinase Inhibitors - administration & dosage; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins p21(ras); ras Proteins - genetics; Signal Transduction - drug effects; TOR Serine-Threonine Kinases - antagonists & inhibitors; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-11-1780

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.