Improved diagnostics targeting c-MET in non-small cell lung cancer: expression, amplification and activation?

Diagnostic Pathology

T. Goldmann⁴  M. Reck²  E. Vollmer⁴  A. Warth¹  D. Jonigk⁵  K. F. Rabe⁴  P. Zabel⁶  M. Thomas¹  R. M. Huber⁷  N. Reinmuth⁴  Ch. Kugler⁴  R. Gaber³  J. Müller⁴  F. Stellmacher⁴  B. Schmitt⁴  I. Watermann⁴ 

[1] Institute of Pathology, Heidelberg University, Heidelberg, Germany;Ludwig Maximilians University (LMU), Munich, Germany;Pathology, Faculty of Medicine, Alexandria University, Alexandria, Egypt;Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Borstel, Germany;Biomedical Research in Endstage and Obstructive Lung Disease Hanover (BREATH), Member of the German Center for Lung Research, Munich, Germany;Medical Clinic, Research Center Borstel, Borstel, Germany;Comprehensive Pneumology Center Munich, (CPC-M), Member of the German Center for Lung Research, Thoracic Oncology Centre Munich, Munich, Germany

关键词: Fluorescence in situ hybridization;    Immunohistochemistry;    Phosphorylated MET;    Diagnostic;    Targeted therapies;    MET;    Non-small cell lung Cancer (NSCLC);   

Others  :  1225936
DOI  :  10.1186/s13000-015-0362-5

 received in 2015-03-23, accepted in 2015-07-09,  发布年份 2015

【 摘 要 】

Background

Several c-MET targeting inhibitory molecules have already shown promising results in the treatment of patients with Non-small Cell Lung Cancer (NSCLC). Combination of EGFR- and c-MET-specific molecules may overcome EGFR tyrosine kinase inhibitor (TKI) resistance. The aim of this study was to allow for the identification of patients who might benefit from TKI treatments targeting MET and to narrow in on the diagnostic assessment of MET.

Methods

222 tumor tissues of patients with NSCLC were analyzed concerning c-MET expression and activation in terms of phosphorylation (Y1234/1235 and Y1349) using a microarray format employing immunohistochemistry (IHC). Furthermore, protein expression and MET activation was correlated with the amplification status by Fluorescence in Situ Hybridization (FISH).

Results

Correlation was observed between phosphorylation of c-MET at Y1234/1235 and Y1349 (spearman correlation coefficient r _s  = 0.41; p < 0.0001). No significant correlation was shown between MET expression and phosphorylation (p > 0.05). c-MET gene amplification was detected in eight of 214 patients (3.7 %). No significant association was observed between c-MET amplification, c-MET protein expression and phosphorylation.

Conclusion

Our data indicate, that neither expression of c-MET nor the gene amplification status might be the best way to select patients for MET targeting therapies, since no correlation with the activation status of MET was observed. We propose to take into account analyzing the phosphorylation status of MET by IHC to select patients for MET targeting therapies. Signaling of the receptor and the activation of downstream molecules might be more crucial for the benefit of therapeutics targeting MET receptor tyrosine kinases than expression levels alone.

【 授权许可】

   
2015 Watermann et al.

【 图 表 】

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