Oncotarget

Research Papers:

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

Shigeki Nanjo, Hiromichi Ebi, Sachiko Arai, Shinji Takeuchi, Tadaaki Yamada, Satsuki Mochizuki, Yasunori Okada, Mitsutoshi Nakada, Takashi Murakami and Seiji Yano _

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Oncotarget. 2016; 7:3847-3856. https://doi.org/10.18632/oncotarget.6758

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Abstract

Shigeki Nanjo1, Hiromichi Ebi1, Sachiko Arai1, Shinji Takeuchi1, Tadaaki Yamada1, Satsuki Mochizuki2, Yasunori Okada2, Mitsutoshi Nakada3, Takashi Murakami4, Seiji Yano1

1Department of Medical Oncology, Kanazawa University Cancer Research Institute, Kanazawa, Japan

2Department of Pathology, Keio University School of Medicine, Tokyo, Japan

3Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan

4Laboratory of Tumor Biology, Takasaki University of Health and Welfare, Takasaki, Japan

Correspondence to:

Seiji Yano, e-mail: syano@staff.kanazawa-u.ac.jp

Keywords: leptomeningeal carcinomatosis, EGFR-TKI resistance, EGFR mutation, EGFR inhibitors

Received: August 06, 2015     Accepted: November 29, 2015     Published: December 24, 2015

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.


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