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 language | English |
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Article number | 4443 |
Journal | Molecules |
Volume | 24 |
Issue number | 24 |
DOIs | |
Publication status | Published - 4 Dec 2019 |
Funding
Funding: This research was funded with a grant from the Institute for Innovation, Science and Technology Flanders (IWT): grant number 121114. E.G. and G.J.P. received grants from the Cancer Center Amsterdam (CCA) Foundation and Polish National Science Center (project 2018/31/B/NZ7/02909). E.G. is funded by the Associazione Italiana per la Ricerca sul Cancro (AIRC Start-Up grant), and KWF Dutch Cancer Society grants (KWF project#10401 and #11957). Conflicts of Interest: Professor Rolfo has received personal fees of Novartis outside the current study. Professor Pauwels has received research funding from Pfizer, Boehringer Ingelheim and Astra Zeneca. Professor Peters had received research funding from Eli Lilly.
Funders | Funder number |
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CCA) Foundation | |
KWF Dutch Cancer Society | |
Associazione Italiana per la Ricerca sul Cancro | |
Pfizer | |
Cancer Center Amsterdam | CCA |
Not added | 11957 |
KWF Kankerbestrijding | #10401 |
Institute for Innovation, Science and Technology Flanders | 121114, IWT |
Polish National Science Center | 2018/31/B/NZ7/02909 |
Keywords
- Biomarkers
- C-Met
- EGFR
- NSCLC