Structural alterations of MET trigger response to MET kinase inhibition in lung adenocarcinoma patients

Dennis Plenker, Miriam Bertrand, Adrianus J. de Langen, Richard Riedel, Carina Lorenz, Andreas H. Scheel, Judith Muller, Johannes Bragelmann, Juliane Daßler-Plenker, Carsten Kobe, Thorsten Persigehl, Alexander Kluge, Thomas Wurdinger, Pepijn Schellen, Gunther Hartmann, Tobias Zacherle, Roopika Menon, Erik Thunnissen, Reinhard Buttner, Frank GriesingerJurgen Wolf, Lukas Heukamp, Martin L. Sos, Johannes M. Heuckmann

Research output: Contribution to journalArticleAcademicpeer-review

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.
Original languageEnglish
Pages (from-to)1337-1343
Number of pages7
JournalClinical Cancer Research
Volume24
Issue number6
DOIs
Publication statusPublished - 2018

Cite this

Plenker, D., Bertrand, M., de Langen, A. J., Riedel, R., Lorenz, C., Scheel, A. H., ... Heuckmann, J. M. (2018). Structural alterations of MET trigger response to MET kinase inhibition in lung adenocarcinoma patients. Clinical Cancer Research, 24(6), 1337-1343. https://doi.org/10.1158/1078-0432.CCR-17-3001