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.

Abstract

Purpose:MET exon 14 deletion (METex14 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 METex14 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 METex14 del-driven patient-derived xenografts, and demonstrated a durable RECIST partial response in a METex14 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 METex14 del/A-loop double mutations and resistance to type I inhibitors exhibited a marked response to glesatinib. Finally, a METex14 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.

• Authors: Lars D Engstrom, Ruth Aranda, Matthew Lee, Elizabeth A Tovar, Curt J Essenburg, Zachary Madaj, Harrah Chiang, David Briere, Jill Hallin, Pedro P Lopez-Casas, Natalia Baños, Camino Menendez, Manuel Hidalgo, Vanessa Tassell, Richard Chao, Darya I Chudova, Richard B Lanman, Peter Olson, Lyudmilla Bazhenova, Sandip Pravin Patel, Carrie Graveel, Mizuki Nishino, Geoffrey I Shapiro, Nir Peled, Mark M Awad, Pasi A Jänne, James G Christensen
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 23 Issue 21 Pg. 6661-6672 (Nov 01 2017) ISSN: 1557-3265 [Electronic] United States
• PMID: 28765324 (Publication Type: Clinical Trial, Phase I, Journal Article)
• Copyright: ©2017 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Benzeneacetamides
• Protein Kinase Inhibitors
• Pyrazoles
• Pyridines
• Crizotinib
• glesatinib
• MET protein, human
• Proto-Oncogene Proteins c-met

Topics

• Adult
• Aged
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Benzeneacetamides (pharmacology, therapeutic use)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, pathology)
• Cell Line, Tumor
• Crizotinib
• Drug Resistance, Neoplasm (drug effects)
• Exons (genetics)
• Female
• Humans
• Liver Neoplasms (drug therapy, genetics, pathology, secondary)
• Male
• Mice
• Middle Aged
• Mutation
• Protein Kinase Inhibitors (administration & dosage, adverse effects)
• Proto-Oncogene Proteins c-met (antagonists & inhibitors, genetics)
• Pyrazoles (administration & dosage)
• Pyridines (administration & dosage, pharmacology, therapeutic use)
• Xenograft Model Antitumor Assays