Cetuximab attenuates metastasis and u-PAR expression in non-small cell lung cancer

U-PAR and E-cadherin are novel biomarkers of cetuximab sensitivity

Dessislava A. Nikolova, Irfan A. Asangani, Laura D. Nelson, Dennis P.M. Hughes, Doris R. Siwak, Gordon Mills, Andrea Harms, Erika Buchholz, Lothar R. Pilz, Christian Manegold, Heike Allgayer

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Cetuximab, which blocks ligand binding to epidermal growth factor receptor (EGFR), is currently being studied as a novel treatment for non-small cell lung cancer (NSCLC). However, its mechanisms of action toward metastasis, and markers of drug sensitivity, have not been fully elucidated. This study was conducted to (a) determine the effect of Cetuximab on invasion and NSCLC-metastasis; (ft) investigate urokinase-type plasminogen activator receptor (u-PAR), a major molecule promoting invasion and metastasis, as a target molecule; (c) delineate molecular mediators of Cetuximab-induced metastasis inhibition; and (d) identify biomarkers of drug sensitivity in NSCLC. Cetuximab treatment resulted in reduced growth and Matrigel invasion of H1395 and A549 NSCLC cell lines, in parallel with reduced u-PAR mRNA and protein. u-PAR down-regulation was brought about by suppressing the binding of JunD and c-Jun to u-PAR promoter motif -190/-171 in vivo, and an inhibition of MAP/ERK kinase signaling. Furthermore, Cetuximab inhibited NSCLC proliferation and metastasis to distant organs in vivo as indicated by the chicken embryo metastasis assay. Low E-cadherin and high u-PAR, but not EGFR, was associated with resistance to Cetuximab in seven NSCLC cell lines. Furthermore, siRNA knockdown of u-PAR led to a resensitization to Cetuximab. Moreover, low E-cadherin and high u-PAR was found in 63% of resected tumor tissues of NSCLC patients progressing under Cetuximab therapy. This is the first study to show u-PAR as a target and marker of sensitivity to Cetuximab, and to delineate novel mechanisms leading to metastasis suppression of NSCLC by Cetuximab.

Original languageEnglish (US)
Pages (from-to)2461-2470
Number of pages10
JournalCancer Research
Volume69
Issue number6
DOIs
StatePublished - Mar 15 2009
Externally publishedYes

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Urokinase Plasminogen Activator Receptors
Cadherins
Non-Small Cell Lung Carcinoma
Biomarkers
Neoplasm Metastasis
Epidermal Growth Factor Receptor
Cetuximab
Cell Line
Mitogen-Activated Protein Kinase Kinases
Pharmaceutical Preparations
Small Interfering RNA
Chickens
Therapeutics
Down-Regulation
Embryonic Structures

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Cetuximab attenuates metastasis and u-PAR expression in non-small cell lung cancer : U-PAR and E-cadherin are novel biomarkers of cetuximab sensitivity. / Nikolova, Dessislava A.; Asangani, Irfan A.; Nelson, Laura D.; Hughes, Dennis P.M.; Siwak, Doris R.; Mills, Gordon; Harms, Andrea; Buchholz, Erika; Pilz, Lothar R.; Manegold, Christian; Allgayer, Heike.

In: Cancer Research, Vol. 69, No. 6, 15.03.2009, p. 2461-2470.

Research output: Contribution to journalArticle

Nikolova, DA, Asangani, IA, Nelson, LD, Hughes, DPM, Siwak, DR, Mills, G, Harms, A, Buchholz, E, Pilz, LR, Manegold, C & Allgayer, H 2009, 'Cetuximab attenuates metastasis and u-PAR expression in non-small cell lung cancer: U-PAR and E-cadherin are novel biomarkers of cetuximab sensitivity', Cancer Research, vol. 69, no. 6, pp. 2461-2470. https://doi.org/10.1158/0008-5472.CAN-08-3236
Nikolova, Dessislava A. ; Asangani, Irfan A. ; Nelson, Laura D. ; Hughes, Dennis P.M. ; Siwak, Doris R. ; Mills, Gordon ; Harms, Andrea ; Buchholz, Erika ; Pilz, Lothar R. ; Manegold, Christian ; Allgayer, Heike. / Cetuximab attenuates metastasis and u-PAR expression in non-small cell lung cancer : U-PAR and E-cadherin are novel biomarkers of cetuximab sensitivity. In: Cancer Research. 2009 ; Vol. 69, No. 6. pp. 2461-2470.
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abstract = "Cetuximab, which blocks ligand binding to epidermal growth factor receptor (EGFR), is currently being studied as a novel treatment for non-small cell lung cancer (NSCLC). However, its mechanisms of action toward metastasis, and markers of drug sensitivity, have not been fully elucidated. This study was conducted to (a) determine the effect of Cetuximab on invasion and NSCLC-metastasis; (ft) investigate urokinase-type plasminogen activator receptor (u-PAR), a major molecule promoting invasion and metastasis, as a target molecule; (c) delineate molecular mediators of Cetuximab-induced metastasis inhibition; and (d) identify biomarkers of drug sensitivity in NSCLC. Cetuximab treatment resulted in reduced growth and Matrigel invasion of H1395 and A549 NSCLC cell lines, in parallel with reduced u-PAR mRNA and protein. u-PAR down-regulation was brought about by suppressing the binding of JunD and c-Jun to u-PAR promoter motif -190/-171 in vivo, and an inhibition of MAP/ERK kinase signaling. Furthermore, Cetuximab inhibited NSCLC proliferation and metastasis to distant organs in vivo as indicated by the chicken embryo metastasis assay. Low E-cadherin and high u-PAR, but not EGFR, was associated with resistance to Cetuximab in seven NSCLC cell lines. Furthermore, siRNA knockdown of u-PAR led to a resensitization to Cetuximab. Moreover, low E-cadherin and high u-PAR was found in 63{\%} of resected tumor tissues of NSCLC patients progressing under Cetuximab therapy. This is the first study to show u-PAR as a target and marker of sensitivity to Cetuximab, and to delineate novel mechanisms leading to metastasis suppression of NSCLC by Cetuximab.",
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AU - Nelson, Laura D.

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AU - Siwak, Doris R.

AU - Mills, Gordon

AU - Harms, Andrea

AU - Buchholz, Erika

AU - Pilz, Lothar R.

AU - Manegold, Christian

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