Poster Presentation 29th Lorne Cancer Conference 2017

Targeting focal adhesion kinase activity in pancreatic cancer (#233)

Kendelle Murphy 1 , Morghan Lucas 1 , Claire Vennin 1 , James Conway 1 , Sean Warren 1 , Romain Bidane 1 , Lisa Horvath 1 , Yingxiao Wang 2 , Owen Sansom 3 , Marina Pajic 1 , Astrid Mangenau 1 , David Herrmann 1 , Paul Timpson 1
  1. Garvan Institute of Medical Research, Darlinghurst, Sydney, NEW SOUTH WALES, Australia
  2. Institute of Engineering in Medicine, University of California, San Diego, CA, USA
  3. Cancer Research UK, Beatson Institute, Glasgow, UK

Pancreatic Ductal Adenocarcinoma (PDAC) is a leading cause of cancer-related deaths worldwide. Despite recent developments in treatment strategies, the 5-year survival rate of 6% has remained unchanged for the past four decades. Consequently, there is a clear need to identify new drugable targets for the clinical management of this aggressive disease.
The multifunctional protein, Focal Adhesion Kinase (FAK), is associated with many aspects of metastasis, such as adhesion, migration and invasion. FAK is often overexpressed or activated in PDAC, and is correlated with patient prognosis. Given this, we elucidate the role of FAK in a primary pancreatic cancer cell line derived from a mouse model of invasive and metastatic PDAC. Using the FAK inhibitor PF-562271, we determined that FAK inhibition in these cells (i.) alters migratory and adhesion patterns on extra-cellular matrix mimics, (ii.) reduces invasion and cell survival, in 3D fibroblast-contacted collagen matrices and (iii.) reduces cell cluster growth in the absence of adhesion. Stromal imaging showed that PF-562271 mediated FAK inhibition suppressed fibroblast-driven ECM remodelling, which may prove beneficial in overcoming the fibrotic PDAC stroma.
The rapid resistance of PDAC to current chemotherapeutics lead to the assessment and identify PF-562271 as a potential sensitiser to the standard-of-care treatments, Gemcitabine and Abraxane. Finally, in order to provide an accurate readout of the dynamic spatiotemporal activity of FAK, a stable cell line expressing the FAK-Fluorescent Resonance Energy Transfer (FRET) biosensor was generated in order to assess the spatiotemporal activity of FAK in real time. Overall, these data reveal the broad functions of FAK in both pancreatic cancer cells and the surrounding microenvironment, thus highlighting its potential as a therapeutic target in the clinical management of PDAC.