TY - JOUR
T1 - Structural alterations of MET trigger response to MET kinase inhibition in lung adenocarcinoma patients
AU - Plenker, Dennis
AU - Bertrand, Miriam
AU - de Langen, Adrianus J.
AU - Riedel, Richard
AU - Lorenz, Carina
AU - Scheel, Andreas H.
AU - Muller, Judith
AU - Bragelmann, Johannes
AU - Daßler-Plenker, Juliane
AU - Kobe, Carsten
AU - Persigehl, Thorsten
AU - Kluge, Alexander
AU - Wurdinger, Thomas
AU - Schellen, Pepijn
AU - Hartmann, Gunther
AU - Zacherle, Tobias
AU - Menon, Roopika
AU - Thunnissen, Erik
AU - Buttner, Reinhard
AU - Griesinger, Frank
AU - Wolf, Jurgen
AU - Heukamp, Lukas
AU - Sos, Martin L.
AU - Heuckmann, Johannes M.
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85048101269&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/29284707
U2 - https://doi.org/10.1158/1078-0432.CCR-17-3001
DO - https://doi.org/10.1158/1078-0432.CCR-17-3001
M3 - Article
C2 - 29284707
SN - 1078-0432
VL - 24
SP - 1337
EP - 1343
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 6
ER -