title: An activation of LC3A-mediated autophagy contributes to de novo and acquired resistance to EGFR tyrosine kinase inhibitors in lung adenocarcinoma.
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.
authors.affiliation: Department of Pathology, School of Medicine, Tohoku University, Sendai, Japan.
authors.forename: Kaito
authors.initials: K
authors.lastname: Nihira
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Miki
authors.forename: Shinya
authors.initials: S
authors.lastname: Iida
authors.forename: Sodai
authors.initials: S
authors.lastname: Narumi
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Ono
authors.forename: Erina
authors.initials: E
authors.lastname: Iwabuchi
authors.forename: Kazue
authors.initials: K
authors.lastname: Ise
authors.forename: Kazushige
authors.initials: K
authors.lastname: Mori
authors.forename: Mikiyoshi
authors.initials: M
authors.lastname: Saito
authors.forename: Masahito
authors.initials: M
authors.lastname: Ebina
authors.forename: Ikuro
authors.initials: I
authors.lastname: Sato
authors.forename: Makoto
authors.initials: M
authors.lastname: Maemondo
authors.forename: Hisafumi
authors.initials: H
authors.lastname: Yamada-Okabe
authors.forename: Takashi
authors.initials: T
authors.lastname: Kondo
authors.forename: Hironobu
authors.initials: H
authors.lastname: Sasano
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D000077192:Adenocarcinoma of Lung; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000235:genetics*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: DNA methylation; EGFR tyrosine kinase inhibitors; autophagy; drug resistance; lung cancer