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Journal of Experimental & Clinical Cancer Research

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Open Access 01-12-2021 | Pancreatic Cancer | Research

Focal adhesion kinase inhibition synergizes with nab-paclitaxel to target pancreatic ductal adenocarcinoma

Authors: T. Y. S. Le Large, M. F. Bijlsma, B. El Hassouni, G. Mantini, T. Lagerweij, A. A. Henneman, N. Funel, B. Kok, T. V. Pham, R. de Haas, L. Morelli, J. C. Knol, S. R. Piersma, G. Kazemier, H. W. M. van Laarhoven, E. Giovannetti, C. R. Jimenez

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2021

Abstract

Background

Pancreatic ductal adenocarcinoma (PDAC) is a very lethal disease, with minimal therapeutic options. Aberrant tyrosine kinase activity influences tumor growth and is regulated by phosphorylation. We investigated phosphorylated kinases as target in PDAC.

Methods

Mass spectrometry-based phosphotyrosine proteomic analysis on PDAC cell lines was used to evaluate active kinases. Pathway analysis and inferred kinase activity analysis was performed to identify novel targets. Subsequently, we investigated targeting of focal adhesion kinase (FAK) in vitro with drug perturbations in combination with chemotherapeutics used against PDAC. Tyrosine phosphoproteomics upon treatment was performed to evaluate signaling. An orthotopic model of PDAC was used to evaluate the combination of defactinib with nab-paclitaxel.

Results

PDAC cell lines portrayed high activity of multiple receptor tyrosine kinases to various degree. The non-receptor kinase, FAK, was identified in all cell lines by our phosphotyrosine proteomic screen and pathway analysis. Targeting of this kinase with defactinib validated reduced phosphorylation profiles. Additionally, FAK inhibition had anti-proliferative and anti-migratory effects. Combination with (nab-)paclitaxel had a synergistic effect on cell proliferation in vitro and reduced tumor growth in vivo.

Conclusions

Our study shows high phosphorylation of several oncogenic receptor tyrosine kinases in PDAC cells and validated FAK inhibition as potential synergistic target with Nab-paclitaxel against this devastating disease.

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Title: Focal adhesion kinase inhibition synergizes with nab-paclitaxel to target pancreatic ductal adenocarcinoma
Authors: T. Y. S. Le Large
M. F. Bijlsma
B. El Hassouni
G. Mantini
T. Lagerweij
A. A. Henneman
N. Funel
B. Kok
T. V. Pham
R. de Haas
L. Morelli
J. C. Knol
S. R. Piersma
G. Kazemier
H. W. M. van Laarhoven
E. Giovannetti
C. R. Jimenez
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Pancreatic Cancer
Pancreatic Cancer
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2021
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-021-01892-z

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Abstract

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