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Oncotarget. 2016 Jan 26;7(4):3847-56. doi: 10.18632/oncotarget.6758.

High efficacy of third generation EGFR inhibitor AZD9291 in a leptomeningeal carcinomatosis model with EGFR-mutant lung cancer cells.

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Department of Medical Oncology, Kanazawa University Cancer Research Institute, Kanazawa, Japan.
Department of Pathology, Keio University School of Medicine, Tokyo, Japan.
Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
Laboratory of Tumor Biology, Takasaki University of Health and Welfare, Takasaki, Japan.


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.


EGFR inhibitors; EGFR mutation; EGFR-TKI resistance; leptomeningeal carcinomatosis

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