title: High efficacy of third generation EGFR inhibitor AZD9291 in a leptomeningeal carcinomatosis model with EGFR-mutant lung cancer cells.
abstract: Leptomeningeal carcinomatosis (LMC) remarkably decreases the quality of life of EGFR-mutant lung cancer patients. In contrast to the lesions outside the central nervous system (CNS), molecular mechanisms of EGFR tyrosine kinase inhibitor (TKI) resistance in CNS lesions including LMC are largely unknown. In this study, we established an in vivo imaging model for LMC with EGFR mutant lung cancer cell lines harboring an exon 19 deletion in EGFR and evaluated the effect of first generation EGFR-TKIs, erlotinib, second generation afatinib, and third generation AZD9291. In PC-9/ffluc model, erlotinib treatment slowed the development of LMC. Importantly, treatment with afatinib or AZD9291 apparently delayed the development of LMC. Moreover, treatment with a higher dose of AZD9291, also associated with inhibited phosphorylation of EGFR downstream molecule S6, regressed LMC refractory to the aforementioned EGFR-TKI treatments. These observations suggest that the third generation EGFR-TKI AZD9291 may be an effective treatment for first or second generation EGFR-TKI resistant LMC caused by EGFR-mutant lung cancer.
authors.affiliation: Department of Medical Oncology, Kanazawa University Cancer Research Institute, Kanazawa, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Nanjo
authors.affiliation: Department of Medical Oncology, Kanazawa University Cancer Research Institute, Kanazawa, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Ebi
authors.affiliation: Department of Medical Oncology, Kanazawa University Cancer Research Institute, Kanazawa, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Arai
authors.affiliation: Department of Medical Oncology, Kanazawa University Cancer Research Institute, Kanazawa, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Takeuchi
authors.affiliation: Department of Medical Oncology, Kanazawa University Cancer Research Institute, Kanazawa, Japan.
authors.forename: Tadaaki
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Department of Pathology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Satsuki
authors.initials: S
authors.lastname: Mochizuki
authors.affiliation: Department of Pathology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Nakada
authors.affiliation: Laboratory of Tumor Biology, Takasaki University of Health and Welfare, Takasaki, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Murakami
authors.affiliation: Department of Medical Oncology, Kanazawa University Cancer Research Institute, Kanazawa, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Yano
mesh_terms: D000178:Acrylamides / Q000494:pharmacology*; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D055756:Meningeal Carcinomatosis / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D051379:Mice; D016513:Mice, SCID; D009154:Mutation / Q000235:genetics*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D007211:Indoles; D011743:Pyrimidines
chemical_list: D000178:Acrylamides; D000814:Aniline Compounds; D066246:ErbB Receptors; D047428:Protein Kinase Inhibitors; C000596361:osimertinib; D007211:Indoles; D011743:Pyrimidines; C512478:EGFR protein, human
keywords: EGFR inhibitors; EGFR mutation; EGFR-TKI resistance; leptomeningeal carcinomatosis