Research Papers:

Novel drug-resistance mechanisms of pemetrexed-treated non-small cell lung cancer

Ryosuke Tanino, Yukari Tsubata, Nanae Harashima, Mamoru Harada and Takeshi Isobe _

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Oncotarget. 2018; 9:16807-16821. https://doi.org/10.18632/oncotarget.24704

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Ryosuke Tanino1, Yukari Tsubata1, Nanae Harashima2, Mamoru Harada3 and Takeshi Isobe1

1Division of Medical Oncology & Respiratory Medicine, Department of Internal Medicine, Faculty of Medicine, Shimane University, Shimane, Japan

2Laboratory of Biometabolic Chemistry, School of Health Sciences, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan

3Department of Immunology, Faculty of Medicine, Shimane University, Shimane, Japan

Correspondence to:

Takeshi Isobe, email: isobeti@med.shimane-u.ac.jp

Keywords: drug resistance; pemetrexed; NSCLC; EGFR-TKI; drug-induced senescence

Received: May 27, 2017    Accepted: March 01, 2018    Published: March 30, 2018


Pemetrexed (PEM) improves the overall survival of patients with advanced non-small cell lung cancer (NSCLC) when administered as maintenance therapy. However, PEM resistance often appears during the therapy. Although thymidylate synthase is known to be responsible for PEM resistance, no other mechanisms have been investigated in detail. In this study, we explored new drug resistance mechanisms of PEM-treated NSCLC using two combinations of parental and PEM-resistant NSCLC cell lines from PC-9 and A549. PEM increased the apoptosis cells in parental PC-9 and the senescent cells in parental A549. However, such changes were not observed in the respective PEM-resistant cell lines. Quantitative RT-PCR analysis revealed that, besides an increased gene expression of thymidylate synthase in PEM-resistant PC-9 cells, the solute carrier family 19 member1 (SLC19A1) gene expression was markedly decreased in PEM-resistant A549 cells. The siRNA-mediated knockdown of SLC19A1 endowed the parental cell lines with PEM resistance. Conversely, PEM-resistant PC-9 cells carrying an epidermal growth factor receptor (EGFR) mutation acquired resistance to a tyrosine kinase inhibitor erlotinib. Although erlotinib can inhibit the phosphorylation of EGFR and Erk, it is unable to suppress the phosphorylation of Akt in PEM-resistant PC-9 cells. Additionally, PEM-resistant PC-9 cells were less sensitive to the PI3K inhibitor LY294002 than parental PC-9 cells. These results indicate that SLC19A1 negatively regulates PEM resistance in NSCLC, and that EGFR-tyrosine-kinase-inhibitor resistance was acquired with PEM resistance through Akt activation in NSCLC harboring EGFR mutations.

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