Her-2/neu-triggered intracellular tyrosine kinase activation: in vivo relevance of ligand-independent activation mechanisms and impact upon the efficacy of trastuzumab-based treatment

G. Hudelist; W. J. Köstler; J. Attems; K. Czerwenka; R. Müller; M. Manavi; G. G. Steger; E. Kubista; C. C. Zielinski; C. F. Singer

doi:10.1038/sj.bjc.6601160

Her-2/neu-triggered intracellular tyrosine kinase activation: in vivo relevance of ligand-independent activation mechanisms and impact upon the efficacy of trastuzumab-based treatment

G. Hudelist
, W. J. Köstler
, J. Attems
, K. Czerwenka
, R. Müller
, M. Manavi
, G. G. Steger
, E. Kubista
, C. C. Zielinski
, C. F. Singer

Universitätsklinik Innsbruck
Allgemeines Krankenhaus
Otto Wagner Hospital
Ludwig-Boltzmann Institute for Clinical Forensic Imaging

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

61 Scopus citations

Abstract

Proteolytic cleavage of the Her-2/neu extracellular domain (ECD) has been shown to initiate receptor phosphorylation representing Her-2/neu/ activation in vitro. The present investigation was performed to evaluate the clinical relevance of ECD cleavage for Her-2/ neu activation and the consequences of active intracellular Her-2/neu signalling reflected by tyrosine kinase phosphorylation in patients treated with the anti-Her-2/neu antibody trastuzumab. Sera from 62 patients receiving trastuzumab-based treatment for Her-2/neu overexpressing metastatic breast cancer were assessed for pretreatment ECD levels using an enzyme-linked immunosorbent assay. In parallel, Her-2/neu activation status of tumour specimens was assessed by immunohistochemistry using a Her-2/neu phosphorylation state specific antibody (PN2A) and correlated with the patients' ECD levels and clinical course of disease. Serum ECD levels were significantly higher in 15 (24%) patients with tumours exhibiting activated Her-2/neu as compared to those without detectable Her-2/neu phosphorylation (median 148.2 vs 28.5 ng ml^-1, P = 0.010). Whereas response rate only showed a trend to be higher in patients with Her-2/neu-phosphorylated breast cancer (47 vs 34%, P = 0.197), both uni- and multivariate analyses revealed that the median progression-free survival under trastuzumab-based treatment was significantly longer in patients with Her-2/neu-phosphorylated breast cancer- 11.7 (95% Cl 5.2-18.3) months-when compared to the progression-free survival of 4.5 (95% Cl 3.4-5.6) months observed in patients with tumours lacking phosphorylated Her-2/neu (P = 0.001). Proteolytic cleavage of the ECD represents a biologically relevant ligand-independent mechanism of Her-2/neu activation in vivo. The influence of Her-2/ neu activation status upon the outcome of trastuzumab-based therapies merits further investigation in larger prospective trials.

Original language	English
Pages (from-to)	983-991
Number of pages	9
Journal	British Journal of Cancer
Volume	89
Issue number	6
DOIs	https://doi.org/10.1038/sj.bjc.6601160
State	Published - 15 Sep 2003
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Breast cancer
Her-2/neu
Trastuzumab
Tyrosine kinase phosphorylation

Access to Document

10.1038/sj.bjc.6601160

Cite this

Hudelist, G., Köstler, W. J., Attems, J., Czerwenka, K., Müller, R., Manavi, M., Steger, G. G., Kubista, E., Zielinski, C. C., & Singer, C. F. (2003). Her-2/neu-triggered intracellular tyrosine kinase activation: in vivo relevance of ligand-independent activation mechanisms and impact upon the efficacy of trastuzumab-based treatment. British Journal of Cancer, 89(6), 983-991. https://doi.org/10.1038/sj.bjc.6601160

@article{67aa62347d464e598221c8f4f5640233,

title = "Her-2/neu-triggered intracellular tyrosine kinase activation: in vivo relevance of ligand-independent activation mechanisms and impact upon the efficacy of trastuzumab-based treatment",

abstract = "Proteolytic cleavage of the Her-2/neu extracellular domain (ECD) has been shown to initiate receptor phosphorylation representing Her-2/neu/ activation in vitro. The present investigation was performed to evaluate the clinical relevance of ECD cleavage for Her-2/ neu activation and the consequences of active intracellular Her-2/neu signalling reflected by tyrosine kinase phosphorylation in patients treated with the anti-Her-2/neu antibody trastuzumab. Sera from 62 patients receiving trastuzumab-based treatment for Her-2/neu overexpressing metastatic breast cancer were assessed for pretreatment ECD levels using an enzyme-linked immunosorbent assay. In parallel, Her-2/neu activation status of tumour specimens was assessed by immunohistochemistry using a Her-2/neu phosphorylation state specific antibody (PN2A) and correlated with the patients' ECD levels and clinical course of disease. Serum ECD levels were significantly higher in 15 (24\%) patients with tumours exhibiting activated Her-2/neu as compared to those without detectable Her-2/neu phosphorylation (median 148.2 vs 28.5 ng ml-1, P = 0.010). Whereas response rate only showed a trend to be higher in patients with Her-2/neu-phosphorylated breast cancer (47 vs 34\%, P = 0.197), both uni- and multivariate analyses revealed that the median progression-free survival under trastuzumab-based treatment was significantly longer in patients with Her-2/neu-phosphorylated breast cancer- 11.7 (95\% Cl 5.2-18.3) months-when compared to the progression-free survival of 4.5 (95\% Cl 3.4-5.6) months observed in patients with tumours lacking phosphorylated Her-2/neu (P = 0.001). Proteolytic cleavage of the ECD represents a biologically relevant ligand-independent mechanism of Her-2/neu activation in vivo. The influence of Her-2/ neu activation status upon the outcome of trastuzumab-based therapies merits further investigation in larger prospective trials.",

keywords = "Breast cancer, Her-2/neu, Trastuzumab, Tyrosine kinase phosphorylation",

author = "G. Hudelist and K{\"o}stler, \{W. J.\} and J. Attems and K. Czerwenka and R. M{\"u}ller and M. Manavi and Steger, \{G. G.\} and E. Kubista and Zielinski, \{C. C.\} and Singer, \{C. F.\}",

year = "2003",

month = sep,

day = "15",

doi = "10.1038/sj.bjc.6601160",

language = "English",

volume = "89",

pages = "983--991",

journal = "British Journal of Cancer",

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publisher = "Springer Nature",

number = "6",

}

Hudelist, G, Köstler, WJ, Attems, J, Czerwenka, K, Müller, R, Manavi, M, Steger, GG, Kubista, E, Zielinski, CC & Singer, CF 2003, 'Her-2/neu-triggered intracellular tyrosine kinase activation: in vivo relevance of ligand-independent activation mechanisms and impact upon the efficacy of trastuzumab-based treatment', British Journal of Cancer, vol. 89, no. 6, pp. 983-991. https://doi.org/10.1038/sj.bjc.6601160

Her-2/neu-triggered intracellular tyrosine kinase activation: in vivo relevance of ligand-independent activation mechanisms and impact upon the efficacy of trastuzumab-based treatment. / Hudelist, G.; Köstler, W. J.; Attems, J. et al.
In: British Journal of Cancer, Vol. 89, No. 6, 15.09.2003, p. 983-991.

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

TY - JOUR

T1 - Her-2/neu-triggered intracellular tyrosine kinase activation

T2 - in vivo relevance of ligand-independent activation mechanisms and impact upon the efficacy of trastuzumab-based treatment

AU - Hudelist, G.

AU - Köstler, W. J.

AU - Attems, J.

AU - Czerwenka, K.

AU - Müller, R.

AU - Manavi, M.

AU - Steger, G. G.

AU - Kubista, E.

AU - Zielinski, C. C.

AU - Singer, C. F.

PY - 2003/9/15

Y1 - 2003/9/15

N2 - Proteolytic cleavage of the Her-2/neu extracellular domain (ECD) has been shown to initiate receptor phosphorylation representing Her-2/neu/ activation in vitro. The present investigation was performed to evaluate the clinical relevance of ECD cleavage for Her-2/ neu activation and the consequences of active intracellular Her-2/neu signalling reflected by tyrosine kinase phosphorylation in patients treated with the anti-Her-2/neu antibody trastuzumab. Sera from 62 patients receiving trastuzumab-based treatment for Her-2/neu overexpressing metastatic breast cancer were assessed for pretreatment ECD levels using an enzyme-linked immunosorbent assay. In parallel, Her-2/neu activation status of tumour specimens was assessed by immunohistochemistry using a Her-2/neu phosphorylation state specific antibody (PN2A) and correlated with the patients' ECD levels and clinical course of disease. Serum ECD levels were significantly higher in 15 (24%) patients with tumours exhibiting activated Her-2/neu as compared to those without detectable Her-2/neu phosphorylation (median 148.2 vs 28.5 ng ml-1, P = 0.010). Whereas response rate only showed a trend to be higher in patients with Her-2/neu-phosphorylated breast cancer (47 vs 34%, P = 0.197), both uni- and multivariate analyses revealed that the median progression-free survival under trastuzumab-based treatment was significantly longer in patients with Her-2/neu-phosphorylated breast cancer- 11.7 (95% Cl 5.2-18.3) months-when compared to the progression-free survival of 4.5 (95% Cl 3.4-5.6) months observed in patients with tumours lacking phosphorylated Her-2/neu (P = 0.001). Proteolytic cleavage of the ECD represents a biologically relevant ligand-independent mechanism of Her-2/neu activation in vivo. The influence of Her-2/ neu activation status upon the outcome of trastuzumab-based therapies merits further investigation in larger prospective trials.

AB - Proteolytic cleavage of the Her-2/neu extracellular domain (ECD) has been shown to initiate receptor phosphorylation representing Her-2/neu/ activation in vitro. The present investigation was performed to evaluate the clinical relevance of ECD cleavage for Her-2/ neu activation and the consequences of active intracellular Her-2/neu signalling reflected by tyrosine kinase phosphorylation in patients treated with the anti-Her-2/neu antibody trastuzumab. Sera from 62 patients receiving trastuzumab-based treatment for Her-2/neu overexpressing metastatic breast cancer were assessed for pretreatment ECD levels using an enzyme-linked immunosorbent assay. In parallel, Her-2/neu activation status of tumour specimens was assessed by immunohistochemistry using a Her-2/neu phosphorylation state specific antibody (PN2A) and correlated with the patients' ECD levels and clinical course of disease. Serum ECD levels were significantly higher in 15 (24%) patients with tumours exhibiting activated Her-2/neu as compared to those without detectable Her-2/neu phosphorylation (median 148.2 vs 28.5 ng ml-1, P = 0.010). Whereas response rate only showed a trend to be higher in patients with Her-2/neu-phosphorylated breast cancer (47 vs 34%, P = 0.197), both uni- and multivariate analyses revealed that the median progression-free survival under trastuzumab-based treatment was significantly longer in patients with Her-2/neu-phosphorylated breast cancer- 11.7 (95% Cl 5.2-18.3) months-when compared to the progression-free survival of 4.5 (95% Cl 3.4-5.6) months observed in patients with tumours lacking phosphorylated Her-2/neu (P = 0.001). Proteolytic cleavage of the ECD represents a biologically relevant ligand-independent mechanism of Her-2/neu activation in vivo. The influence of Her-2/ neu activation status upon the outcome of trastuzumab-based therapies merits further investigation in larger prospective trials.

KW - Breast cancer

KW - Her-2/neu

KW - Trastuzumab

KW - Tyrosine kinase phosphorylation

UR - https://www.scopus.com/pages/publications/0141956319

U2 - 10.1038/sj.bjc.6601160

DO - 10.1038/sj.bjc.6601160

M3 - Article

C2 - 12966413

AN - SCOPUS:0141956319

SN - 0007-0920

VL - 89

SP - 983

EP - 991

JO - British Journal of Cancer

JF - British Journal of Cancer

IS - 6

ER -

Her-2/neu-triggered intracellular tyrosine kinase activation: in vivo relevance of ligand-independent activation mechanisms and impact upon the efficacy of trastuzumab-based treatment

Abstract

UN SDGs

Keywords

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