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M. Harada

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    P1.02 - Biology/Pathology (ID 614)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P1.02-069 - Pemetrexed-Resistant Non-Small Cell Lung Cancer Cell Lines Have Novel Drug-Resistant Mechanisms (ID 7366)

      09:30 - 16:00  |  Author(s): M. Harada

      • Abstract

      Pemetrexed (PEM) is an anti-folate drug that is widely used as a first-line chemotherapy for non-squamous non-small cell lung cancer (NSCLC) without epidermal growth factor receptor (EGFR) mutation that treated with EGFR tyrosine kinase inhibitors (TKIs). Beyond that, PEM has still important role for second- or third-line chemotherapy after the occurring EGFR-TKI resistant mutations. While several proteins such as a folate enzyme thymidylate synthase (TYMS) were reported as contributing factors of PEM resistance in NSCLC cells, we still need a maker with high specificity for drug sensitivity to PEM to use in clinical setting. We aimed finding novel factors of PEM-resistance by using NSCLC cell lines in vitro.

      We established two different sets of PEM resistant NSCLC cell lines by long-term continuously PEM exposure in vitro from those parental cell lines A549 and PC-9. We analyzed the effects of PEM in those parental and resistant cell lines, also identified mechanisms of the resistance in PEM-resistant cell lines by molecular-biological analysis.

      One of the PEM-resistant cell line that is derived from A549 has obviously decreased mRNA expression of a folate transporter protein SLC19A1 in qRT-PCR analysis. Additionally, we also confirmed that the siRNA knockdown of SLC19A1 endowed parental NSCLC cell lines with PEM resistance. Surprisingly, another PEM-resistant cell line derived from EGFR mutant PC-9 has not only the significantly increased TYMS that is most reported protein in PEM-resistant NSCLC cell lines but also EGFR-independent Akt activation on PI3K signaling pathway. Importantly, this Akt activation carried low sensitivity to EGFR-TKI and PI3K inhibitor in the PEM-resistant PC-9 cells.

      In conclusion, SLC19A1 negatively regulates PEM resistance in NSCLC cell lines and long-term PEM treatment encompasses EGFR-TKI resistance in EGFR mutant NSCLC cell line.