The role of c-met as a biomarker and player in innate and acquired resistance in non-small-cell lung cancer: Two new mutations warrant further studies

Nele Van Der Steen, Karen Zwaenepoel, Giulia Mazzaschi, Rosa A. Luirink, Daan P. Geerke, Ken Op De Beeck, Christophe Hermans, Marcello Tiseo, Paul Van Schil, Filip Lardon, Paul Germonpré, Christian Rolfo, Elisa Giovannetti, Godefridus J. Peters, Patrick Pauwels*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

The c-Met receptor is a therapeutically actionable target in non-small-cell lung cancer (NSCLC), with one approved drug and several agents in development. Most suitable biomarkers for patient selection include c-Met amplification and exon-14 skipping. Our retrospective study focused on the frequency of different c-Met aberrations (overexpression, amplification and mutations) in 153 primary, therapy-naïve resection samples and their paired metastases, from Biobank@UZA. Furthermore, we determined the correlation of c-Met expression with clinicopathological factors, Epidermal Growth Factor Receptor (EGFR)-status and TP53 mutations. Our results showed that c-Met expression levels in primary tumors were comparable to their respective metastases. Five different mutations were detected by deep sequencing: Three (E168D, S203T, N375S) previously described and two never reported (I333T, G783E). I333T, a new mutation in the Sema(phorin) domain of c-Met, might influence the binding of antibodies targeting the HGF-binding domain, potentially causing innate resistance. E168D and S203T mutations showed a trend towards a correlation with high c-Met expression (p = 0.058). We found a significant correlation between c-MET expression, EGFR expression (p = 0.010) and EGFR mutations (p = 0.013), as well as a trend (p = 0.057) with regards to TP53 mutant activity. In conclusion this study demonstrated a strong correlation between EGFR mutations, TP53 and c-Met expression in therapy-naïve primary resection samples. Moreover, we found two new c-Met mutations that warrant further studies.

Original languageEnglish
Article number4443
JournalMolecules
Volume24
Issue number24
DOIs
Publication statusPublished - 4 Dec 2019

Keywords

  • Biomarkers
  • C-Met
  • EGFR
  • NSCLC

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