Research output: Contribution to journal › Article › Academic › peer-review
Focal adhesion kinase inhibition synergizes with nab-paclitaxel to target pancreatic ductal adenocarcinoma. / le Large, T. Y. S.; Bijlsma, M. F.; el Hassouni, B. et al.
In: Journal of experimental & clinical cancer research, Vol. 40, No. 1, 91, 01.12.2021.Research output: Contribution to journal › Article › Academic › peer-review
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TY - JOUR
T1 - Focal adhesion kinase inhibition synergizes with nab-paclitaxel to target pancreatic ductal adenocarcinoma
AU - le Large, T. Y. S.
AU - Bijlsma, M. F.
AU - el Hassouni, B.
AU - Mantini, G.
AU - Lagerweij, T.
AU - Henneman, A. A.
AU - Funel, N.
AU - Kok, B.
AU - Pham, T. V.
AU - de Haas, R.
AU - Morelli, L.
AU - Knol, J. C.
AU - Piersma, S. R.
AU - Kazemier, G.
AU - van Laarhoven, H. W. M.
AU - Giovannetti, E.
AU - Jimenez, C. R.
N1 - Funding Information: Cancer Center Amsterdam Alliantie-AIO grant (EG, MB, CJ), Bennink Foundation (GK, EG and TL), Dutch Cancer Society (#10212; CJ, MB, and EG, and #11975; EG), Italian Association for Cancer Research AIRC/IG grant, Italy (EG), Netherlands Organization for Scientific Research (NWO- Middelgroot project number 91116017, CJ) is acknowledged for support of the mass spectrometry infrastructure. Funding Information: HvL received research funding from Bayer, BMS, Lilly, Nordic Pharma and Servier. None of these parties were involved in drafting this manuscript or involved with study design. Publisher Copyright: © 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
KW - EPHA2
KW - FAK
KW - MET
KW - Pancreatic cancer
KW - Phosphoproteomics
KW - Therapy
UR - http://www.scopus.com/inward/record.url?scp=85102552220&partnerID=8YFLogxK
U2 - 10.1186/s13046-021-01892-z
DO - 10.1186/s13046-021-01892-z
M3 - Article
C2 - 33750427
VL - 40
JO - Journal of experimental & clinical cancer research
JF - Journal of experimental & clinical cancer research
SN - 0392-9078
IS - 1
M1 - 91
ER -
ID: 17469292