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Molecular imaging of Akt kinase activity

Nature Medicine volume 13, pages 1114–1119 (2007)Cite this article

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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Figure 1: BAR reporter.
Figure 2: Time- and dose-dependent imaging of Akt activity.
Figure 3: Phosphorylation and specificity of BAR.
Figure 4: Molecular imaging of Akt.

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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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Authors and Affiliations

  1. Department of Radiation Oncology, University of Michigan, Ann Arbor, 48109, Michigan, USA

    Limin Zhang, Mahaveer S Bhojani, Amjad P Khan, Alla Shilman & Alnawaz Rehemtulla

  2. Department of Radiology, University of Michigan, Ann Arbor, 48109, Michigan, USA

    Kuei C Lee & Brian D Ross

  3. Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, 10021, New York, USA

    Eric C Holland

  4. Center for Molecular Imaging, University of Michigan, Ann Arbor, 48109, Michigan, USA

    Brian D Ross & Alnawaz Rehemtulla

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  1. Limin Zhang
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Contributions

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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Correspondence to Alnawaz Rehemtulla.

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The authors declare no competing financial interests.

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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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