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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

Center for Oncological Research, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium
Department of Pathology, Antwerp University Hospital, Wilrijkstraat 10, 2650 Antwerp, Belgium
Department of Medical Oncology, VU University Medical Center, CCA 1.42, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
Department of Medicine and Surgery, University of Parma and Medical Oncology Unit, University Hospital of Parma, 43126 Parma, Italy
AIMMS Division of Molecular Toxicology, Department of Chemistry and Pharmaceutical Sciences, Faculty of Sciences, VU University Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands
Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, 2650 Antwerp, Belgium
Department of Thoracic and Vascular Surgery, University Hospital, Wilrijkstraat 10, 2650 Antwerp, Belgium
Department of Pneumology, AZ Maria Middelares, Kliniekstraat 27, 9050 Gentbrugge, Belgium
Phase I-Early Clinical Trials Unit, Oncology Department, Antwerp University Hospital, Wilrijkstraat 10, 2650 Antwerp, Belgium
Thoracic Medical Oncology, Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD 20742, USA
Cancer Pharmacology Lab, AIRC Start-Up Unit, Fondazione Pisana per la Scienza, Via Giovannini 13, San Giuliano Terme, I-56017 Pisa, Italy
Department of Biochemistry, Medical University of Gdansk, 80-844 Gdansk, Poland
Authors to whom correspondence should be addressed.
Molecules 2019, 24(24), 4443;
Received: 16 October 2019 / Revised: 27 November 2019 / Accepted: 28 November 2019 / Published: 4 December 2019
(This article belongs to the Special Issue Drug Resistance in Targeted Cancer Therapy)
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 [email protected] 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. View Full-Text
Keywords: NSCLC; c-Met; EGFR; biomarkers NSCLC; c-Met; EGFR; biomarkers
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Van Der Steen, N.; Zwaenepoel, K.; Mazzaschi, G.; A. Luirink, R.; P. Geerke, D.; Op de Beeck, K.; Hermans, C.; Tiseo, M.; Van Schil, P.; Lardon, F.; Germonpré, P.; Rolfo, C.; Giovannetti, E.; J. Peters, G.; Pauwels, P. 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. Molecules 2019, 24, 4443.

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