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Open AccessArticle

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

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Center for Oncological Research, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium
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Department of Pathology, Antwerp University Hospital, Wilrijkstraat 10, 2650 Antwerp, Belgium
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Department of Medical Oncology, VU University Medical Center, CCA 1.42, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
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Department of Medicine and Surgery, University of Parma and Medical Oncology Unit, University Hospital of Parma, 43126 Parma, Italy
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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
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Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, 2650 Antwerp, Belgium
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Department of Thoracic and Vascular Surgery, University Hospital, Wilrijkstraat 10, 2650 Antwerp, Belgium
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Department of Pneumology, AZ Maria Middelares, Kliniekstraat 27, 9050 Gentbrugge, Belgium
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Phase I-Early Clinical Trials Unit, Oncology Department, Antwerp University Hospital, Wilrijkstraat 10, 2650 Antwerp, Belgium
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Thoracic Medical Oncology, Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD 20742, USA
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Cancer Pharmacology Lab, AIRC Start-Up Unit, Fondazione Pisana per la Scienza, Via Giovannini 13, San Giuliano Terme, I-56017 Pisa, Italy
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Department of Biochemistry, Medical University of Gdansk, 80-844 Gdansk, Poland
*
Authors to whom correspondence should be addressed.
Molecules 2019, 24(24), 4443; https://doi.org/10.3390/molecules24244443
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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