Christine M. Chresta

AstraZeneca (United Kingdom)

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Sarah Runswick

Bioscience Research

Garry Beran

AstraZeneca (United Kingdom)

Tim French

University of Western Australia

Paul D. Smith

Swedish University of Agricultural Sciences

Chris Harbron

Roche (United Kingdom)

Jonathan R. Dry

AstraZeneca (United States)

Rose McCormack

AstraZeneca (United Kingdom)

Neal Rosen

Memorial Sloan Kettering Cancer Center

Mark Cockerill

Bioscience Research

Leisl Packer

QIMR Berghofer Medical Research Institute

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AstraZeneca (United Kingdom)

134

GW Pharmaceuticals (United Kingdom)

University of Manchester

AstraZeneca (Brazil)

Memorial Sloan Kettering Cancer Center

Cancer Research UK

University of Oxford

AstraZeneca (United States)

University College London

Array BioPharma (United States)

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

Sarah V. Holt Armelle Logié Barry R. Davies Denis Alférez Sarah Runswick

<div>AbstractThe 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.</div>

Selumetinib

10.1158/0008-5472.c.6503583

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Supplementary Table 4 from Transcriptional Pathway Signatures Predict MEK Addiction and Response to Selumetinib (AZD6244)

Jonathan R. Dry Sandra Pavey Christine A. Pratilas Chris Harbron Sarah Runswick

Supplementary Table 4 from Transcriptional Pathway Signatures Predict MEK Addiction and Response to Selumetinib (AZD6244)

Selumetinib

10.1158/0008-5472.22386749

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Supplementary Table 4 from Transcriptional Pathway Signatures Predict MEK Addiction and Response to Selumetinib (AZD6244)