Author of

• 18971

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  P1.02 - Biology/Pathology (ID 614)

  • Event: WCLC 2017
  • Type: Poster Session with Presenters Present
  • Track: Biology/Pathology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)

  • 22553

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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 - 09:30  |  Author(s): N. Harashima
    • Abstract

    Background:
    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.
    
    Method:
    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.
    
    Result:
    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.
    
    Conclusion:
    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.