| Status | 已發表Published |
| Characterization of osimertinib (AZD9291)-resistant non-small-cell lung cancer NCI-H1975/OSIR cell line | |
Tang, ZH ; Jiang, XM; Guo, X; Fong, CM; Wang, ZY; Chen, X. P.; Lu, J. 
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| 2016-10-01 | |
| Source Publication | The 9th Chinese Conference on Oncology & the 15th Cross-Strait Academic Conference on Oncology
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| Abstract | Purpose: The osimertinib (OSI) is the newest FDA-approved third generation of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) for non-small-cell lung cancer (NSCLC) patients with EGFR T790M mutation. However, resistance to OSI is likely to progress by experience from previous EGFR TKI. Therefore, study the resistant mechanisms of OSI in advance is important to direct the future development of EGFR TKI. Methods: The OSI resistant NCI-H1975 cells (NCI-H1975/OSIR) were established by dosage escalation manner. The MTT and colony formation assays were used to confirm the resistant effects of NCI-H1975/OSIR to OSI. The biological properties of NCI-H1975/OSIR cells in terms of proliferation, migration, and invasion were detected by MTT, western blot, and transwell assays. The sensitivity of NCI-H1975 and NCI-H1975/OSIR cells to other EGFR TKIs and chemotherapeutics were studied by MTT assay. The EGFR and downstream of EGFR were examined by western blot and RT-PCR methods. The MTT, colony formation, annexin V FITC/PI, and western blot methods were used to detect the sensitivity of ABT-263 in NCI-H1975 and NCI-H1975/OSIR cells. Results: Compared with NCI-H1975 cells, NCI-H1975/OSIR cells displayed more resistance to OSI by MTT and colony formation assays. After resistance to OSI, cell proliferation was decreased while cell migration and invasion were increased. The NCI-H1975/OSIR cells exhibited more resistance to getinifib, erlotinib, afatinib, rociletinib, doxorubicin, and fluorouracil, while more sensitivity to paclitaxel and pemetrexed, compared with that of parent cells. Furthermore, the phosphorylated, total, and mRNA expressions of EGFR were decreased after cells resistance to OSI, and the EGFR downstream pathway Erk and Akt in NCI-H1975/OSIR cells could not be 3 inhibited by OSI treatment. Compared with the parent cells, the cell viability inhibition and apoptosis of ABT-263 in NCI-H1975/OSIR cells shown more significant, and the cell viability inhibition and apoptosis of ABT-263 in NCI-H1975/OSIR cells could be reversed by pretreatment of pan-caspase inhibitor Z-VAD-FMK. Conclusion: Acquire resistance to OSI with decreased cell proliferation and increased cell migration and invasion. Downregulation of EGFR might be the potential mechanism for NCI-H1975 cells resistance to OSI and the ABT-263 might be the candidate drug for treatment of NSCLC patients after acquired resistance to OSI. |
| Keyword | osimertinib resistance EGFR ABT-263 |
| Language | 英語English |
| The Source to Article | PB_Publication |
| PUB ID | 36494 |
| Document Type | Conference paper |
| Collection | Institute of Chinese Medical Sciences |
| Corresponding Author | Lu, J. |
| Recommended Citation GB/T 7714 | Tang, ZH,Jiang, XM,Guo, X,et al. Characterization of osimertinib (AZD9291)-resistant non-small-cell lung cancer NCI-H1975/OSIR cell line[C], 2016. |
| APA | Tang, ZH., Jiang, XM., Guo, X., Fong, CM., Wang, ZY., Chen, X. P.., & Lu, J. (2016). Characterization of osimertinib (AZD9291)-resistant non-small-cell lung cancer NCI-H1975/OSIR cell line. The 9th Chinese Conference on Oncology & the 15th Cross-Strait Academic Conference on Oncology. |
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