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

Takuya Shintani,Masanori Obana,Atsushi Kumanogoh,Ryosuke Tsuji,Yasuo Tsutsumi,Eiichi Morii,Atsuhiro Sato,Shinichiro Maeda,Yuri Kashiwagi,Yuhei Kinehara,Kazuma Higashisaka,Makiko Maeda,Yasushi Fujio,Ying Lin,Koudai Kurihara,Izumi Nagatomo,Takashi Kijima,Yoshiro Miwa ,Koichiro Kawasaki ,Masahiko Hamada ,Ai Yamamoto

doi:10.18632/oncotarget.26494

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.

Highlights

In spite of the recent advances in molecular targeted therapy, lung cancer remains the leading cause of cancerrelated death worldwide [1]
We found that LC3B-II was upregulated in PC9/ER cells, while downregulated by the knockdown of eukaryotic translation initiation factor 3 subunit C (eIF3c)
We identified eIF3c as a novel molecule involved in Epidermal growth factor receptor (EGFR)-TKI resistance acquisition by newly establishing EGFR-TKI resistant cells, PC9/ER cells

Summary

Introduction

In spite of the recent advances in molecular targeted therapy, lung cancer remains the leading cause of cancerrelated death worldwide [1]. Epidermal growth factor receptor (EGFR) is the main oncogenic driver in nonsmall cell lung cancer (NSCLC). Previous retrospective analyses have reported EGFR over-expression in 62% of NSCLC cases, and its expression is correlated with a poor prognosis [2]. The phosphorylation of EGFR initiates downstream pathways, such as Ras/extracellular signalregulated kinase 1 and 2 (ERK1/2), phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (mTOR), and Janus kinase 2/signal transducer and activator of transcription 3, leading to carcinogenesis by promoting cell proliferation, survival, invasion and metastasis [3]. In NSCLC patients, somatic mutations in EGFR gene, most commonly deletions in exon 19 (delE746-A750) or substitution of arginine for leucine (L858R) in exon 21, are observed in ~10% of cases in North America and Western Europe, and ~30–50% in East Asian descent [4,5,6]. Lung tumors inevitably acquire resistance to these EGFR-TKIs around 12 months [11]

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Results

Conclusion