title: METCopy Number Gain Is Associated with Gefitinib Resistance in Leptomeningeal Carcinomatosis ofEGFR-mutant Lung Cancer.
abstract: Leptomeningeal carcinomatosis occurs frequently inEGFR-mutant lung cancer, and develops acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). This study aimed to clarify the mechanism of EGFR-TKI resistance in leptomeningeal carcinomatosis and seek for a novel therapeutic strategy. We examinedEGFRmutations, including the T790M gatekeeper mutation, in 32 re-biopsy specimens from 12 leptomeningeal carcinomatosis and 20 extracranial lesions ofEGFR-mutant lung cancer patients who became refractory to EGFR-TKI treatment. All the 32 specimens had the same baselineEGFRmutations, but the T790M mutation was less frequent in leptomeningeal carcinomatosis specimens than in extracranial specimens (8% vs. 55%,P< 0.01). To study molecular mechanisms of acquired EGFR-TKI resistance in leptomeningeal carcinomatosis, we utilized our previously developed mouse model of leptomeningeal carcinomatosis with theEGFR-mutant lung cancer cell line PC-9/ffluc cells, in which acquired resistance to gefitinib was induced by continuous oral treatment. Compared with subcutaneously inoculated gefitinib-resistant tumors, the T790M mutation was less frequent in leptomeningeal carcinomatosis that acquired resistance to gefitinib. PC-9/LMC-GR cells were established from the gefitinib-resistant leptomeningeal carcinomatosis model, and they were found to be intermediately resistant to gefitinib and osimertinib (third-generation EGFR-TKI). AlthoughEGFR-T790M was negative, gefitinib resistance of PC-9/LMC-GR cells was related toMETcopy number gain with MET activation. Moreover, combined use of EGFR-TKI and crizotinib, a MET inhibitor, dramatically regressed leptomeningeal carcinomatosis with acquired resistance to gefitinib or osimertinib. These findings suggest that combination therapy with MET inhibitors may be promising for controlling leptomeningeal carcinomatosis that acquires resistance to EGFR-TKIs.Mol Cancer Ther; 16(3); 506-15. ©2017 AACR.
authors.affiliation: Division of Medical Oncology, Kanazawa University Cancer Research Institute, Kanazawa, Japan.|Division of Integrated Oncology, Institute of Biomedical Research and Innovation, Chuo-ku, Kobe, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Nanjo
authors.affiliation: Division of Medical Oncology, Kanazawa University Cancer Research Institute, Kanazawa, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Arai
authors.affiliation: Division of Medical Oncology, Kanazawa University Cancer Research Institute, Kanazawa, Japan.|Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Division of Medical Oncology, Kanazawa University Cancer Research Institute, Kanazawa, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Takeuchi
authors.affiliation: Division of Medical Oncology, Kanazawa University Cancer Research Institute, Kanazawa, Japan.
authors.forename: Tadaaki
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Division of Integrated Oncology, Institute of Biomedical Research and Innovation, Chuo-ku, Kobe, Japan.
authors.forename: Akito
authors.initials: A
authors.lastname: Hata
authors.affiliation: Division of Integrated Oncology, Institute of Biomedical Research and Innovation, Chuo-ku, Kobe, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Katakami
authors.affiliation: Department of Pathology, Keio University School of Medicine, Tokyo, Japan.|Department of Pathophysiology for Locomotive and Neoplastic Diseases, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Division of Medical Oncology, Kanazawa University Cancer Research Institute, Kanazawa, Japan. syano@staff.kanazawa-u.ac.jp.
authors.forename: Seiji
authors.initials: S
authors.lastname: Yano
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D000077156:Gefitinib; D018628:Gene Dosage; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics; D055756:Meningeal Carcinomatosis / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D051379:Mice; D009154:Mutation; D016609:Neoplasms, Second Primary; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D011799:Quinazolines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D000077156:Gefitinib