1. Glesatinib Exhibits Antitumor Activity in Lung Cancer Models and Patients Harboring MET Exon 14 Mutations and Overcomes Mutation-mediated Resistance to Type I MET Inhibitors in Nonclinical Models.
- Author
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Engstrom LD, Aranda R, Lee M, Tovar EA, Essenburg CJ, Madaj Z, Chiang H, Briere D, Hallin J, Lopez-Casas PP, Baños N, Menendez C, Hidalgo M, Tassell V, Chao R, Chudova DI, Lanman RB, Olson P, Bazhenova L, Patel SP, Graveel C, Nishino M, Shapiro GI, Peled N, Awad MM, Jänne PA, and Christensen JG
- Subjects
- Adult, Aged, Animals, Antineoplastic Agents pharmacology, Benzeneacetamides pharmacology, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Cell Line, Tumor, Crizotinib, Exons genetics, Female, Humans, Liver Neoplasms genetics, Liver Neoplasms pathology, Liver Neoplasms secondary, Male, Mice, Middle Aged, Mutation, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors adverse effects, Proto-Oncogene Proteins c-met genetics, Pyrazoles administration & dosage, Pyridines administration & dosage, Pyridines pharmacology, Xenograft Model Antitumor Assays, Antineoplastic Agents therapeutic use, Benzeneacetamides therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Drug Resistance, Neoplasm drug effects, Liver Neoplasms drug therapy, Proto-Oncogene Proteins c-met antagonists & inhibitors, Pyridines therapeutic use
- Abstract
Purpose: MET exon 14 deletion ( MET ex14 del) mutations represent a novel class of non-small cell lung cancer (NSCLC) driver mutations. We evaluated glesatinib, a spectrum-selective MET inhibitor exhibiting a type II binding mode, in MET ex14 del-positive nonclinical models and NSCLC patients and assessed its ability to overcome resistance to type I MET inhibitors. Experimental Design: As most MET inhibitors in clinical development bind the active site with a type I binding mode, we investigated mechanisms of acquired resistance to each MET inhibitor class utilizing in vitro and in vivo models and in glesatinib clinical trials. Results: Glesatinib inhibited MET signaling, demonstrated marked regression of MET ex14 del-driven patient-derived xenografts, and demonstrated a durable RECIST partial response in a MET ex14 del mutation-positive patient enrolled on a glesatinib clinical trial. Prolonged treatment of nonclinical models with selected MET inhibitors resulted in differences in resistance kinetics and mutations within the MET activation loop (i.e., D1228N, Y1230C/H) that conferred resistance to type I MET inhibitors, but remained sensitive to glesatinib. In vivo models exhibiting MET ex14 del/A-loop double mutations and resistance to type I inhibitors exhibited a marked response to glesatinib. Finally, a MET ex14 del mutation-positive NSCLC patient who responded to crizotinib but later relapsed, demonstrated a mixed response to glesatinib including reduction in size of a MET Y1230H mutation-positive liver metastasis and concurrent loss of detection of this mutation in plasma DNA. Conclusions: Together, these data demonstrate that glesatinib exhibits a distinct mechanism of target inhibition and can overcome resistance to type I MET inhibitors. Clin Cancer Res; 23(21); 6661-72. ©2017 AACR ., (©2017 American Association for Cancer Research.)
- Published
- 2017
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