PO-229 Transient tissue ‘priming’ via FAK inhibition to impair pancreatic ductal adenocarcinoma (PDAC) progression to improve sensitivity to gemcitabine/abraxane

• Published in: ESMO open 2018-07, Vol.3 (Suppl 2), p.A316-A317
• Main Authors: Murphy, K, Vennin, C, Cox, T, Wang, Y, Morton, J, Sansom, O, Pajic, M, Herrmann, D, Timpson, P
• Format: Article
• Language: English
• ISSN: 2059-7029; 2059-7029
• DOI: 10.1136/esmoopen-2018-EACR25.746

IntroductionThe extensive stromal deposition and remodelling of pancreatic ductal adenocarcinoma (PDAC) alters mechanical tumour-stroma integrations, promoting tumour development and metastatic spread. Few effective therapies mean that PDAC is predicted to be the second leading cause of cancer mortality by 2030. In highly metastatic mouse models of PDAC, we observed enhanced extracellular matrix (ECM) deposition and remodelling throughout disease progression. This was paralleled by an increased focal adhesion kinase (FAK) expression and activity, suggesting a role for FAK in the increased desmoplastic reaction that is typical of PDAC. Consequently, fine tuned manipulation of the dense stroma by streamlined FAK inhibition (FAKi) presents a novel opportunity for PDAC management and improved response to chemotherapy.Material and methodsIntravital imaging of the FUCCI cell cycle reporter was used to dynamically monitor tumour cell response to combined FAKi and standard-of-care therapy with gemcitabine/Abraxane. This was overlaid with second harmonic generation (SHG) imaging of collagen fibres, to assess the efficacy of FAKi to disrupt the dense PDAC ECM. To complement our in vivo metastatic studies, we used sophisticated 3D in vitro models of invasion, anchorage-independent growth and shear-stress, in both primary and patient-derived PDAC cell lines.Results and discussionsWe systematically demonstrated that using FAKi to modulate ECM prior to standard-of-care therapy enhanced treatment efficacy whilst also reducing metastatic spread in vivo. Further analysis revealed that FAKi sensitised cells to shear stress, impairing metastatic colonisation and the establishment of fibrotic niches in the liver. Stratified patient samples revealed a subset of patients likely to respond to FAK priming regimes, where fine-tuned ECM manipulation prior to chemotherapy may offer a novel opportunity in metastatic PDAC.ConclusionThis subtype-specific fine-tuned stromal manipulation may allow us to maximise gemcitabine/Abraxane therapy whilst reducing drug toxicity and potentially reducing metastatic spread in a preclinical setting.