Structural alterations of MET trigger response to MET kinase inhibition in lung adenocarcinoma patients
| Autor: | Dennis Plenker, Erik Thunnissen, Pepijn Schellen, Judith Müller, Lukas C. Heukamp, Miriam Bertrand, Jürgen Wolf, Tobias Zacherle, Martin L. Sos, Carsten Kobe, Gunther Hartmann, Juliane Daßler-Plenker, Richard Riedel, Reinhard Büttner, Roopika Menon, Johannes M. Heuckmann, Frank Griesinger, Thomas Wurdinger, Carina Lorenz, Andreas H. Scheel, Johannes Brägelmann, Thorsten Persigehl, Adrianus J. de Langen, Alexander Kluge |
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| Přispěvatelé: | Pulmonary medicine, CCA - Cancer biology and immunology, Neurosurgery, VU University medical center, Pathology |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Adult Male Cancer Research Oncogene Proteins Fusion Adenocarcinoma of Lung 03 medical and health sciences 0302 clinical medicine Crizotinib Gene Duplication Medicine Humans Anaplastic Lymphoma Kinase Protein Interaction Domains and Motifs Molecular Targeted Therapy Lung cancer Protein Kinase Inhibitors Neoplasm Staging Gene Rearrangement Ceritinib business.industry Kinase Cancer Gene rearrangement Middle Aged Proto-Oncogene Proteins c-met medicine.disease Immunohistochemistry 030104 developmental biology Oncology Protein kinase domain 030220 oncology & carcinogenesis Cancer research Adenocarcinoma Female business Tomography X-Ray Computed medicine.drug Protein Binding |
| Zdroj: | Clinical Cancer Research, 24(6), 1337-1343. American Association for Cancer Research Inc. 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 2018, ' Structural alterations of MET trigger response to MET kinase inhibition in lung adenocarcinoma patients ', Clinical Cancer Research, vol. 24, no. 6, pp. 1337-1343 . https://doi.org/10.1158/1078-0432.CCR-17-3001 |
| ISSN: | 1078-0432 |
| Popis: | 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. ©2017 AACR. |
| Databáze: | OpenAIRE |
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