PAK1 mediates pancreatic cancer cell migration and resistance to MET inhibition.
作者： Wei Zhou , Adrian M Jubb , Karen Lyle , Qian Xiao , Christy C Ong
DOI: 10.1002/PATH.4412
关键词:
摘要: Pancreatic adenocarcinoma (PDAC) is a major unmet medical need and deeper understanding of molecular drivers needed to advance therapeutic options for patients. We report here that p21-activated kinase 1 (PAK1) central node in PDAC cells downstream multiple growth factor signalling pathways, including hepatocyte (HGF) MET receptor tyrosine kinase. PAK1 inhibition blocks cytoskeletal effectors tumour cell motility driven by HGF/MET. antagonists, such as onartuzumab crizotinib, are currently clinical development. Given even highly effective therapies have resistance mechanisms, we show combination with overcomes potential mechanisms mediated either activation parallel pathways or direct amplification PAK1. Inhibition attenuated vivo metastasis model pancreatic adenocarcinoma. In human tissues, expressed proportion PDACs (33% IHC score 2 3; n = 304) its expression significantly associated positivity (p < 0.0001) linked widespread metastatic pattern patients 0.067). Taken together, our results provide evidence functional role MET/PAK1 support further characterization inhibitors this indication.
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