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Monitoring the dynamics of Src activity in response to anti-invasive dasatinib treatment at a subcellular level using dual intravital imaging

Abstract

Optimising response to tyrosine kinase inhibitors in cancer remains an extensive field of research. Intravital imaging is an emerging tool, which can be used in drug discovery to facilitate and fine-tune maximum drug response in live tumors. A greater understanding of intratumoural delivery and pharmacodynamics of a drug can be obtained by imaging drug target-specific fluorescence resonance energy transfer (FRET) biosensors in real time. Here, we outline our recent work using a Src-FRET biosensor as a readout of Src activity to gauge optimal tyrosine kinase inhibition in response to dasatinib treatment regimens in vivo. By simultaneously monitoring both the inhibition of Src using FRET imaging, and the modulation of the surrounding extracellular matrix using second harmonic generation (SHG) imaging, we were able to show enhanced drug penetrance and delivery to live pancreatic tumors. We discuss the implications of this dual intravital imaging approach in the context of altered tumor-stromal interactions, while summarising how this approach could be applied to assess other combination strategies or tyrosine kinase inhibitors in a preclinical setting.

Type Journal
ISBN 1933-6926 (Electronic) 1933-6918 (Linking)
Authors Nobis, M.; McGhee, E. J.; Herrmann, D.; Magenau, A.; Morton, J. P.; Anderson, K. I.; Timpson, P.;
Responsible Garvan Author A/Prof Paul Timpson
Publisher Name Cell Adhesion & Migration
Published Date 2014-01-01
Published Volume 8
Published Issue 5
Published Pages 478-86
Status Published in-print
URL link to publisher's version http://www.ncbi.nlm.nih.gov/pubmed/25482620
OpenAccess link to author's accepted manuscript version https://publications.gimr.garvan.org.au/open-access/12683