PAK1 mediates pancreatic cancer cell migration and resistance to MET inhibition

Wei Zhou, Adrian M. Jubb, Karen Lyle, Qian Xiao, Christy C. Ong, Rupal Desai, Ling Fu, Florian Gnad, Qinghua Song, Peter M. Haverty, Daniela Aust, Robert Grützmann, Mally Romero, Klara Totpal, Richard M. Neve, Yibing Yan, William F. Forrest, Yulei Wang, Rajiv Raja, Christian PilarskyAna De Jesus-Acosta, Marcia Belvin, Lori S. Friedman, Mark Merchant, Elizabeth M. Jaffee, Lei Zheng, Hartmut Koeppen, Klaus P. Hoeflich

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)502-513
Number of pages12
JournalJournal of Pathology
Volume234
Issue number4
DOIs
StatePublished - Dec 1 2014

Keywords

  • GDC-0941 (pictilisib)
  • MET
  • Onartuzumab
  • PAK1
  • Pancreatic adenocarcinoma

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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