The combination of AZD8055 and selumetinib (AZD6244, ARRY-142886) is synergistic in a subset of non small cell lung cancer cell lines with co-dependancy to the MEK and mTOR pathways.


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Zoe Howard1, Jonathan Dry1, Gayle Marshall1, Nicola Curtis1, Sylvie Guichard1, Paul Smith1
1AstraZeneca, Cheshire, United Kingdom

Background

The PI3K/AKT/mTOR and Ras/Raf/MEK/ERK pathways are frequently de-regulated in cancer. These two signalling cascades interact at several nodes and share both inputs and a common set of downstream targets. Inhibition of both signalling networks may therefore be necessary to result in optimal therapeutic benefit. This may be particularly important in tumours with genetic abnormalities in these pathways (KRas, PI3K or LKB1 mutations) such as non small cell lung cancer. To test this hypothesis, the combination of the selective mTOR kinase inhibitor AZD8055, and MEK1/2 inhibitor selumetinib was evaluated in a large panel of non small cell lung cancer cell lines.

Method

This in vitro study was carried out using a panel of 34 cell lines selected on the basis of their MEK functional output and mutational status. Biomarker analysis of the ERK and mTOR pathways was undertaken using ELISA-based assays and immunoblotting. The combination effects of a concurrent exposure to AZD8055 and selumetinib was assessed using an Acumen Explorer based Sytox-green assay, measuring both cell proliferation and cell death. In particular, a phenotypic switch between growth inhibition with single agent to cell death with the combination was explored.

Results

AZD8055 inhibited both mTORC1 (pS6, p4EBP1) and mTORC2 (pAKT) biomarkers while AZD6244 decreased pERK in a concentration-dependent manner. However, in some cell lines feedback activation of AKT and ERK was observed following exposure to selumetinib or AZD8055 monotherapy, respectively. This feedback activation was abrogated with the combination. A subset of cell lines demonstrated a phenotypic switch or a significant synergistic effect with the combination of AZD8055 and AZD6244.

Conclusion

Both the genetic status and the MEK signature are potential markers of the combination effect and could be instrumental for the clinical development of this combination.