Eukaryotic translation initiation factor 3 subunit C is associated with acquired resistance to erlotinib in non-small cell lung cancer

// Takuya Shintani 1, 2 , Kazuma Higashisaka 1, 3 , Makiko Maeda 1 , Masaya Hamada 1 , Ryosuke Tsuji 1 , Koudai Kurihara 1 , Yuri Kashiwagi 1 , Atsuhiro Sato 1 , Masanori Obana 1 , Ayaha Yamamoto 1 , Keisuke Kawasaki 4 , Ying Lin 1 , Takashi Kijima 5, 6 , Yuhei Kinehara 6 , Yoshihiro Miwa 2 , Shinichiro Maeda 1, 2 , Eiichi Morii 4 , Atsushi Kumanogoh 6, 7 , Yasuo Tsutsumi 1, 8 , Izumi Nagatomo 6 and Yasushi Fujio 1, 7 1 Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan 2 Department of Pharmacy, Osaka University Hospital, Suita, Japan 3 Department of Legal Medicine, Osaka University Graduate School of Medicine, Suita, Japan 4 Department of Pathology, Osaka University Graduate School of Medicine, Suita, Japan 5 Division of Respiratory Medicine, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan 6 Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Japan 7 Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Japan 8 The Center for Advanced Medical Engineering and Informatics, Osaka University, Suita, Japan Correspondence to: Yasushi Fujio, email: fujio@phs.osaka-u.ac.jp Keywords: eukaryotic translation initiation factor 3 subunit C (eIF3c); non-small cell lung cancer (NSCLC); epidermal growth factor receptor (EGFR); EGFR-TKI resistance; autophagy Received: August 29, 2018      Accepted: December 10, 2018      Published: December 25, 2018 ABSTRACT The acquisition of resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) is one of the major problems in the pharmacotherapy against non-small cell lung cancers; however, molecular mechanisms remain to be fully elucidated. Here, using a newly-established erlotinib-resistant cell line, PC9/ER, from PC9 lung cancer cells, we demonstrated that the expression of translation-related molecules, including eukaryotic translation initiation factor 3 subunit C (eIF3c), was upregulated in PC9/ER cells by proteome analyses. Immunoblot analyses confirmed that eIF3c protein increased in PC9/ER cells, compared with PC9 cells. Importantly, the knockdown of eIF3c with its siRNAs enhanced the drug sensitivity in PC9/ER cells. Mechanistically, we found that LC3B-II was upregulated in PC9/ER cells, while downregulated by the knockdown of eIF3c. Consistently, the overexpression of eIF3c increased the number of autophagosomes, proposing the causality between eIF3c expression and autophagy. Moreover, chloroquine, an autophagy inhibitor, restored the sensitivity to erlotinib. Finally, immunohistochemical analyses of biopsy samples showed that the frequency of eIF3c-positive cases was higher in the patients with EGFR-TKI resistance than those prior to EGFR-TKI treatment. Moreover, the eIF3c-positive cases exhibited poor prognosis in EGFR-TKI treatment. Collectively, the upregulation of eIF3c could impair the sensitivity to EGFR-TKI as a novel mechanism of the drug resistance.