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.
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 / Van Der Steen, N.; Zwaenepoel, K.; Mazzaschi, G.; Luirink, R. A.; Geerke, D. P.; De Beeck, K. O.; Hermans, C.; Tiseo, M.; Van Schil, P.; Lardon, F.; Germonpre, P.; Rolfo, C.; Giovannetti, E.; Peters, G. J.; Pauwels, P.. - In: MOLECULES. - ISSN 1420-3049. - 24:24(2019), p. 4443. [10.3390/molecules24244443]
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