Universität zu Köln

Plenker, Dennis, Bertrand, Miriam, de Langen, Adrianus J., Riedel, Richard, Lorenz, Carina, Scheel, Andreas H., Mueller, Judith, Braegelmann, Johannes, Dassler-Plenker, Juliane, Kobe, Carsten, Persigehl, Thorsten, Kluge, Alexander, Wurdinger, Thomas, Schellen, Pepijn, Hartmann, Gunther ORCID: 0000-0003-1021-2018, Zacherle, Tobias, Menon, Roopika, Thunnissen, Erik, Buettner, Reinhard, Griesinger, Frank, Wolf, Juergen, Heukamp, Lukas ORCID: 0000-0002-3388-3482, Sos, Martin L. and Heuckmann, Johannes M. (2018). Structural Alterations of MET Trigger Response to MET Kinase Inhibition in Lung Adenocarcinoma Patients. Clin. Cancer Res., 24 (6). S. 1337 - 1344. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1557-3265

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Abstract

Purpose: We sought to investigate the clinical response to MET inhibition in patients diagnosed with structural MET alterations and to characterize their functional relevance in cellular models. Experimental Design: Patients were selected for treatment with crizotinib upon results of hybrid capture-based next-generation sequencing. To confirm the clinical observations, we analyzed cellular models that express these MET kinase alterations. Results: Three individual patients were identified to harbor alterations within the MET receptor. Two patients showed genomic rearrangements, leading to a gene fusion of KIF5B or STARD3NL and MET. One patient diagnosed with an EML4-ALK rearrangement developed a MET kinase domain duplication as a resistance mechanism to ceritinib. All 3 patients showed a partial response to crizotinib that effectively inhibits MET and ALK among other kinases. The results were further confirmed using orthogonal cellular models. Conclusions: Crizotinib leads to a clinical response in patients with MET rearrangements. Our functional analyses together with the clinical data suggest that these structural alterations may represent actionable targets in lung cancer patients. (C) 2017 AACR.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Plenker, Dennis UNSPECIFIED UNSPECIFIED UNSPECIFIED Bertrand, Miriam UNSPECIFIED UNSPECIFIED UNSPECIFIED de Langen, Adrianus J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Riedel, Richard UNSPECIFIED UNSPECIFIED UNSPECIFIED Lorenz, Carina UNSPECIFIED UNSPECIFIED UNSPECIFIED Scheel, Andreas H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mueller, Judith UNSPECIFIED UNSPECIFIED UNSPECIFIED Braegelmann, Johannes UNSPECIFIED UNSPECIFIED UNSPECIFIED Dassler-Plenker, Juliane UNSPECIFIED UNSPECIFIED UNSPECIFIED Kobe, Carsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Persigehl, Thorsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Kluge, Alexander UNSPECIFIED UNSPECIFIED UNSPECIFIED Wurdinger, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Schellen, Pepijn UNSPECIFIED UNSPECIFIED UNSPECIFIED Hartmann, Gunther UNSPECIFIED orcid.org/0000-0003-1021-2018 UNSPECIFIED Zacherle, Tobias UNSPECIFIED UNSPECIFIED UNSPECIFIED Menon, Roopika UNSPECIFIED UNSPECIFIED UNSPECIFIED Thunnissen, Erik UNSPECIFIED UNSPECIFIED UNSPECIFIED Buettner, Reinhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Griesinger, Frank UNSPECIFIED UNSPECIFIED UNSPECIFIED Wolf, Juergen UNSPECIFIED UNSPECIFIED UNSPECIFIED Heukamp, Lukas UNSPECIFIED orcid.org/0000-0002-3388-3482 UNSPECIFIED Sos, Martin L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Heuckmann, Johannes M. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-192657
DOI:	10.1158/1078-0432.CCR-17-3001
Journal or Publication Title:	Clin. Cancer Res.
Volume:	24
Number:	6
Page Range:	S. 1337 - 1344
Date:	2018
Publisher:	AMER ASSOC CANCER RESEARCH
Place of Publication:	PHILADELPHIA
ISSN:	1557-3265
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CANCER; RESISTANCE; FUSIONS; LANDSCAPE; THERAPY; DOMAIN; TARGET Multiple languages Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/19265