Combining inhibitors of the mTOR (AZD8055) and MEK1/2 (AZD6244; ARRY-142886) pathways demonstrates enhanced apoptotic signalling and tumour growth inhibition in human tumour xenograft models


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Sarah Holt2, Nicola Curtis1, Armelle Logie1, Patrizia Sini1, Barry Davies1, Christine Chresta1, Sylvie Guichard1, Paul Smith1, Robert Wilkinson1

1AstraZeneca, Alderley Edge, UK, 2Paterson Institute for Cancer Research, Manchester, UK

Abstract

Cancers frequently exhibit multiple de-regulated growth factor signalling pathways that in many cases are the result of somatic mutations in pathway components. The most frequently activated of these pathways are the PI3K/AKT/mTOR and Ras/Raf/MEK/ERK pathways. These two pathways share inputs and outputs and also interact at multiple nodes leading to an increased likelihood of redundancy and innate resistance. In panels comprising both human lung (NSCLC) and colorectal cell-lines and cell-derived xenografts, we investigated the consequences of combination therapy, using an mTOR (mTORC1/2) kinase inhibitor and the MEK1/2 inhibitor, AZD6244 (ARRY-142886).

Synergistic combination interactions were identified across a panel of human lung carcinoma cell lines when combining AZD6244 in-vitro concurrently with an mTOR inhibitor.