Publication date: 12 June 2018
Source:Cell Reports, Volume 23, Issue 11
Author(s): James R.W. Conway, Sean C. Warren, David Herrmann, Kendelle J. Murphy, Aurélie S. Cazet, Claire Vennin, Robert F. Shearer, Monica J. Killen, Astrid Magenau, Pauline Mélénec, Mark Pinese, Max Nobis, Anaiis Zaratzian, Alice Boulghourjian, Andrew M. Da Silva, Gonzalo del Monte-Nieto, Arne S.A. Adam, Richard P. Harvey, Jody J. Haigh, Yingxiao Wang, David R. Croucher, Owen J. Sansom, Marina Pajic, C. Elizabeth Caldon, Jennifer P. Morton, Paul Timpson
Application of advanced intravital imaging facilitates dynamic monitoring of pathway activity upon therapeutic inhibition. Here, we assess resistance to therapeutic inhibition of the PI3K pathway within the hypoxic microenvironment of pancreatic ductal adenocarcinoma (PDAC) and identify a phenomenon whereby pronounced hypoxia-induced resistance is observed for three clinically relevant inhibitors. To address this clinical problem, we have mapped tumor hypoxia by both immunofluorescence and phosphorescence lifetime imaging of oxygen-sensitive nanoparticles and demonstrate that these hypoxic regions move transiently around the tumor. To overlay this microenvironmental information with drug response, we applied a FRET biosensor for Akt activity, which is a key effector of the PI3K pathway. Performing dual intravital imaging of drug response in different tumor compartments, we demonstrate an improved drug response to a combination therapy using the dual mTORC1/2 inhibitor AZD2014 with the hypoxia-activated pro-drug TH-302.
Graphical abstract
Teaser
Intravital imaging facilitates the real-time tracking and targeting of moving hypoxic regions within pancreatic ductal adenocarcinoma. Using this approach, Conway et al. alleviate hypoxia-induced resistance to a dual mTORC1/2 inhibitor AZD2014, improving PI3K pathway inhibition and demonstrating a powerful dual imaging modality applicable to targeting other pathways and cancers.https://ift.tt/2HOqcHK
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