Abstract
The serine/threonine kinase Akt mediates mitogenic and anti-apoptotic responses that result from activation of multiple signaling cascades. It is considered a key determinant of tumor aggressiveness and is a major target for anticancer drug development. Here, we describe a new reporter molecule whose bioluminescence activity within live cells and in mice can be used to measure Akt activity. Akt activity in cultured cells and tumor xenografts was monitored quantitatively and dynamically in response to activation or inhibition of receptor tyrosine kinase, inhibition of phosphoinositide 3-kinase, or direct inhibition of Akt. The results provide unique insights into the pharmacokinetics and pharmacodynamics of agents that modulate Akt activity, revealing the usefulness of this reporter for rapid dose and schedule optimization in the drug development process.
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Acknowledgements
We thank members of the Center for Molecular Imaging and the Department of Radiation Oncology at the University of Michigan for their help and support. We thank Genentech for erlotinib. This work was supported by US National Institutes of Health grants P01CA85878, P50CA01014 and R24CA83099.
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L.Z. conducted the majority of the experiments, with help from K.C.L. (in vivo studies), M.S.B., A.P.K. and A.S. (in vitro studies). E.C.H. and B.D.R. provided routine guidance; A.R. supervised the project and wrote the manuscript.
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Zhang, L., Lee, K., Bhojani, M. et al. Molecular imaging of Akt kinase activity. Nat Med 13, 1114–1119 (2007). https://doi.org/10.1038/nm1608
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DOI: https://doi.org/10.1038/nm1608
