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 Pilarsky; Ana De Jesus-Acosta; Marcia Belvin; Lori S. Friedman; Mark Merchant; Elizabeth M. Jaffee; Lei Zheng; Hartmut Koeppen; Klaus P. Hoeflich

doi:10.1002/path.4412

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

School of Medicine

Research output: Contribution to journal › Article › peer-review

32 Scopus citations

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 language	English (US)
Pages (from-to)	502-513
Number of pages	12
Journal	Journal of Pathology
Volume	234
Issue number	4
DOIs	https://doi.org/10.1002/path.4412
State	Published - Dec 1 2014

Keywords

GDC-0941 (pictilisib)
MET
Onartuzumab
PAK1
Pancreatic adenocarcinoma

ASJC Scopus subject areas

Pathology and Forensic Medicine

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10.1002/path.4412

Cite this

Zhou, W., Jubb, A. M., Lyle, K., Xiao, Q., Ong, C. C., Desai, R., Fu, L., Gnad, F., Song, Q., Haverty, P. M., Aust, D., Grützmann, R., Romero, M., Totpal, K., Neve, R. M., Yan, Y., Forrest, W. F., Wang, Y., Raja, R., ... Hoeflich, K. P. (2014). PAK1 mediates pancreatic cancer cell migration and resistance to MET inhibition. Journal of Pathology, 234(4), 502-513. https://doi.org/10.1002/path.4412

Zhou, W, Jubb, AM, Lyle, K, Xiao, Q, Ong, CC, Desai, R, Fu, L, Gnad, F, Song, Q, Haverty, PM, Aust, D, Grützmann, R, Romero, M, Totpal, K, Neve, RM, Yan, Y, Forrest, WF, Wang, Y, Raja, R, Pilarsky, C, De Jesus-Acosta, A, Belvin, M, Friedman, LS, Merchant, M, Jaffee, EM, Zheng, L, Koeppen, H & Hoeflich, KP 2014, 'PAK1 mediates pancreatic cancer cell migration and resistance to MET inhibition', Journal of Pathology, vol. 234, no. 4, pp. 502-513. https://doi.org/10.1002/path.4412

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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.",

keywords = "GDC-0941 (pictilisib), MET, Onartuzumab, PAK1, Pancreatic adenocarcinoma",

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

note = "Publisher Copyright: Copyright {\textcopyright} 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.",

year = "2014",

month = dec,

day = "1",

doi = "10.1002/path.4412",

language = "English (US)",

volume = "234",

pages = "502--513",

journal = "Journal of Pathology",

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T1 - PAK1 mediates pancreatic cancer cell migration and resistance to MET inhibition

AU - Zhou, Wei

AU - Jubb, Adrian M.

AU - Lyle, Karen

AU - Xiao, Qian

AU - Ong, Christy C.

AU - Desai, Rupal

AU - Fu, Ling

AU - Gnad, Florian

AU - Song, Qinghua

AU - Haverty, Peter M.

AU - Aust, Daniela

AU - Grützmann, Robert

AU - Romero, Mally

AU - Totpal, Klara

AU - Neve, Richard M.

AU - Yan, Yibing

AU - Forrest, William F.

AU - Wang, Yulei

AU - Raja, Rajiv

AU - Pilarsky, Christian

AU - De Jesus-Acosta, Ana

AU - Belvin, Marcia

AU - Friedman, Lori S.

AU - Merchant, Mark

AU - Jaffee, Elizabeth M.

AU - Zheng, Lei

AU - Koeppen, Hartmut

AU - Hoeflich, Klaus P.

PY - 2014/12/1

Y1 - 2014/12/1

N2 - 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.

AB - 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.

KW - GDC-0941 (pictilisib)

KW - MET

KW - Onartuzumab

KW - PAK1

KW - Pancreatic adenocarcinoma

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U2 - 10.1002/path.4412

DO - 10.1002/path.4412

M3 - Article

C2 - 25074413

AN - SCOPUS:84910665838

SN - 0022-3417

VL - 234

SP - 502

EP - 513

JO - Journal of Pathology

JF - Journal of Pathology

IS - 4

ER -

PAK1 mediates pancreatic cancer cell migration and resistance to MET inhibition

Abstract

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