Pancreatic adenocarcinoma (PDAC) is a major unmet medical need and a deeper 
understanding of molecular drivers is needed to advance therapeutic options for 
patients. We report here that p21-activated kinase 1 (PAK1) is a central node in 
PDAC cells downstream of multiple growth factor signalling pathways, including 
hepatocyte growth factor (HGF) and MET receptor tyrosine kinase. PAK1 inhibition 
blocks signalling to cytoskeletal effectors and tumour cell motility driven by 
HGF/MET. MET antagonists, such as onartuzumab and crizotinib, are currently in 
clinical development. Given that even highly effective therapies have resistance 
mechanisms, we show that combination with PAK1 inhibition overcomes potential 
resistance mechanisms mediated either by activation of parallel growth factor 
pathways or by direct amplification of PAK1. Inhibition of PAK1 attenuated in 
vivo tumour growth and metastasis in a model of pancreatic adenocarcinoma. In 
human tissues, PAK1 is highly expressed in a proportion of PDACs (33% IHC score 
2 or 3; n = 304) and its expression is significantly associated with MET 
positivity (p < 0.0001) and linked to a widespread metastatic pattern in 
patients (p = 0.067). Taken together, our results provide evidence for a 
functional role of MET/PAK1 signalling in pancreatic adenocarcinoma and support 
further characterization of therapeutic inhibitors in this indication.