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P1.02 - Biology/Pathology (ID 614)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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
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.