An activation of LC3A-mediated autophagy contributes to de novo and acquired resistance to EGFR tyrosine kinase inhibitors in lung adenocarcinoma

Kaito Nihira, Yasuhiro Miki, Shinya Iida, Sodai Narumi, Katsuhiko Ono, Erina Iwabuchi, Kazue Ise, Kazushige Mori, Mikiyoshi Saito, Masahito Ebina, Ikuro Sato, Makoto Maemondo, Hisafumi Yamada-Okabe, Takashi Kondo, Hironobu Sasano

Research output: Contribution to journalArticlepeer-review

31 Citations (Scopus)

Abstract

The development of therapeutic resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs, ie erlotinib or gefitinib) has been the major clinical problem when treating lung adenocarcinoma patients with these agents. However, its mechanisms have not necessarily been well studied to this date. Autophagy has been recently considered to play pivotal roles in escaping from the effects of anti-neoplastic agents. Therefore, in this study, we examined its roles in the development of resistance to EGFR-TKIs in lung adenocarcinoma. We first established erlotinib-resistant cell lines (PC9/ER) from parental PC9 cells by exposing the cells to erlotinib. In PC9/ER, autophagy-related LC3A expression came to be up-regulated and constitutive activation of LC3A-mediated autophagy became more pronounced through the process of acquiring therapeutic resistance. In addition, inhibition of LC3A or autophagy restores sensitivity to EGFR-TKIs in PC9/ER. LC3A was also activated at the transcriptional level in de novo resistant cells via demethylation of the MAP1LC3A gene. We then evaluated the status of LC3A in 169 lung adenocarcinoma patients using immunohistochemistry. LC3A immunoreactivity was only detected in carcinoma cells (89/169 patients), not in non-tumoural cells. In addition, LC3A immunoreactivity was significantly correlated with progression-free survival (p = 0.0039) and overall survival (p = 0.0040) of 35 patients treated with EGFR-TKIs. The results of our present study demonstrated that LC3A-mediated autophagy in carcinoma cells was involved in the development of resistance to EGFR-TKIs, and that LC3A could serve as a promising therapeutic target for overcoming resistance to EGFR-TKIs and a novel predictor of response to EGFR-TKIs in lung adenocarcinoma patients.

Original languageEnglish
Pages (from-to)277-288
Number of pages12
JournalJournal of Pathology
Volume234
Issue number2
DOIs
Publication statusPublished - 2014 Oct 1

Keywords

  • Autophagy
  • DNA methylation
  • Drug resistance
  • EGFR tyrosine kinase inhibitors
  • Lung cancer

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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