title: PAK1 mediates pancreatic cancer cell migration and resistance to MET inhibition.
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.
authors: Department of Translational Oncology, Genentech, Inc, South San Francisco, CA 94080, USA.
authors: Wei
authors: W
authors: Zhou
authors: Adrian M
authors: AM
authors: Jubb
authors: Karen
authors: K
authors: Lyle
authors: Qian
authors: Q
authors: Xiao
authors: Christy C
authors: CC
authors: Ong
authors: Rupal
authors: R
authors: Desai
authors: Ling
authors: L
authors: Fu
authors: Florian
authors: F
authors: Gnad
authors: Qinghua
authors: Q
authors: Song
authors: Peter M
authors: PM
authors: Haverty
authors: Daniela
authors: D
authors: Aust
authors: Robert
authors: R
authors: Grützmann
authors: Mally
authors: M
authors: Romero
authors: Klara
authors: K
authors: Totpal
authors: Richard M
authors: RM
authors: Neve
authors: Yibing
authors: Y
authors: Yan
authors: William F
authors: WF
authors: Forrest
authors: Yulei
authors: Y
authors: Wang
authors: Rajiv
authors: R
authors: Raja
authors: Christian
authors: C
authors: Pilarsky
authors: Ana
authors: A
authors: de Jesus-Acosta
authors: Marcia
authors: M
authors: Belvin
authors: Lori S
authors: LS
authors: Friedman
authors: Mark
authors: M
authors: Merchant
authors: Elizabeth M
authors: EM
authors: Jaffee
authors: Lei
authors: L
authors: Zheng
authors: Hartmut
authors: H
authors: Koeppen
authors: Klaus P
authors: KP
authors: Hoeflich
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001384:Azetidines / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D010880:Piperidines / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D054462:p21-Activated Kinases / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D001384:Azetidines; D010880:Piperidines; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; C515903:PAK1 protein, human; D054462:p21-Activated Kinases; C574276:cobimetinib; C584058:onartuzumab
keywords: GDC-0941 (pictilisib); MET; PAK1; onartuzumab; pancreatic adenocarcinoma