Structural Alterations of MET Trigger Response to MET Kinase Inhibition in Lung Adenocarcinoma Patients

Plenker, D., Bertrand, M., de Langen, A. J., Riedel, R., Lorenz, C., Scheel, A. H., Muller, J., Bragelmann, J., Dassler-Plenker, J., Kobe, C., Persigehl, T., Kluge, A., Wurdinger, T., Schellen, P., Hartmann, G., Zacherle, T., Menon, R., Thunnissen, E., Buttner, R., Griesinger, F., Wolf, J., Heukamp, L., Sos, M. L., Heuckmann, J. M. (March 2018) Structural Alterations of MET Trigger Response to MET Kinase Inhibition in Lung Adenocarcinoma Patients. Clin Cancer Res, 24 (6). pp. 1337-1343. ISSN 1078-0432 (Print)1078-0432

URL: https://www.ncbi.nlm.nih.gov/pubmed/29284707
DOI: 10.1158/1078-0432.ccr-17-3001

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. Clin Cancer Res; 24(6); 1337-43. (c)2017 AACR.

Item Type: Paper
Subjects: diseases & disorders > cancer > cancer types > lung cancer
CSHL Authors:
Communities: CSHL labs > Tuveson lab
Depositing User: Matt Covey
Date: 15 March 2018
Date Deposited: 20 Jun 2018 20:22
Last Modified: 20 Jun 2018 20:22
Related URLs:
URI: http://repository.cshl.edu/id/eprint/36749

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