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, Seiji Yano

Research output: Contribution to journalArticle

43 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3847-3856
Number of pages10
JournalOncotarget
Volume7
Issue number4
DOIs
Publication statusPublished - 2016

Fingerprint

Meningeal Carcinomatosis
Lung Neoplasms
Protein-Tyrosine Kinases
Central Nervous System
Therapeutics
S 6
Cohort Effect
AZD9291
Exons
Phosphorylation
Quality of Life
Cell Line

Keywords

  • EGFR inhibitors
  • EGFR mutation
  • EGFR-TKI resistance
  • Leptomeningeal carcinomatosis

ASJC Scopus subject areas

  • Oncology

Cite this

High efficacy of third generation EGFR inhibitor AZD9291 in a leptomeningeal carcinomatosis model with EGFR-mutant lung cancer cells. / Nanjo, Shigeki; Ebi, Hiromichi; Arai, Sachiko; Takeuchi, Shinji; Yamada, Tadaaki; Mochizuki, Satsuki; Okada, Yasunori; Nakada, Mitsutoshi; Murakami, Takashi; Yano, Seiji.

In: Oncotarget, Vol. 7, No. 4, 2016, p. 3847-3856.

Research output: Contribution to journalArticle

Nanjo, S, Ebi, H, Arai, S, Takeuchi, S, Yamada, T, Mochizuki, S, Okada, Y, Nakada, M, Murakami, T & Yano, S 2016, 'High efficacy of third generation EGFR inhibitor AZD9291 in a leptomeningeal carcinomatosis model with EGFR-mutant lung cancer cells', Oncotarget, vol. 7, no. 4, pp. 3847-3856. https://doi.org/10.18632/oncotarget.6758
Nanjo, Shigeki ; Ebi, Hiromichi ; Arai, Sachiko ; Takeuchi, Shinji ; Yamada, Tadaaki ; Mochizuki, Satsuki ; Okada, Yasunori ; Nakada, Mitsutoshi ; Murakami, Takashi ; Yano, Seiji. / High efficacy of third generation EGFR inhibitor AZD9291 in a leptomeningeal carcinomatosis model with EGFR-mutant lung cancer cells. In: Oncotarget. 2016 ; Vol. 7, No. 4. pp. 3847-3856.
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