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

• Published in: Molecules (Basel, Switzerland) Switzerland), 2019-12, Vol.24 (24), p.4443
• Main Authors: Van Der Steen, Nele, Zwaenepoel, Karen, Mazzaschi, Giulia, A Luirink, Rosa, P Geerke, Daan, Op de Beeck, Ken, Hermans, Christophe, Tiseo, Marcello, Van Schil, Paul, Lardon, Filip, Germonpré, Paul, Rolfo, Christian, Giovannetti, Elisa, J Peters, Godefridus, Pauwels, Patrick
• Format: Article
• Language: English
• Subjects: Adult; Aged; Biomarkers; Biomarkers, Tumor - metabolism; Cancer therapies; Carcinoma, Non-Small-Cell Lung - genetics; Clinical trials; Crosstalk; Drug Resistance, Neoplasm - genetics; Epidermal growth factor receptors; ErbB Receptors - genetics; Female; Fluorescence; Fluorescence in situ hybridization; Gene Amplification; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Lung cancer; Lung Neoplasms - genetics; Lymphatic system; Lymphoma; Male; Metastasis; Middle Aged; Monoclonal antibodies; Mutation; Mutation - genetics; Neoplasm Metastasis; Non-small cell lung carcinoma; Patients; Proteins; Proto-Oncogene Proteins c-met - genetics; Tumor Suppressor Protein p53 - genetics; Tumors
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules24244443

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 ( = 0.058). We found a significant correlation between c-MET expression, EGFR expression ( = 0.010) and mutations ( = 0.013), as well as a trend ( = 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.