| Autor: |
Liu, Dongcheng, Liu, Hongguang, Gan, Jiadi, Zeng, Shinuan, Zhong, Fuhua, Zhang, Bin, Zhang, Zhe, Zhang, Siyu, Jiang, Lu, Wang, Guangsuo, Chen, Yixin, Kong, Feng-Ming Spring, Fang, Wenfeng, Wang, Lingwei |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
Frontiers in Pharmacology. 13 |
| ISSN: |
1663-9812 |
| DOI: |
10.3389/fphar.2022.918317 |
| Popis: |
Non-small cell lung carcinoma (NSCLC) patients who initially received tyrosine kinase inhibitor (TKI) therapy often acquired resistance via multiple complex mechanisms. The amplification of FGF3/4/19/CCND1 on chromosome 11q13 was found in many cancers with TKI resistance. However, the role of these amplifications in TKI-resistant NSCLC remains uncovered. Here, we generated the FGF3/4/19/CCND1 amplification model in the NSCLC cell lines PC-9 and HCC827. Upregulation of FGF3/4/19/CCND1 strongly promoted cell proliferation and gefitinib resistance in NSCLC cells. To find out the potential therapeutic strategies, we screened the combination of inhibitors against the FGF/FGFR signaling pathway and the CCND1/CDK4 complex and revealed that gefitinib combined with LY2874455 and abemaciclib exhibited the most effective inhibition of resistance in vitro and in vivo. Mechanistically, FGFs/CCND1 activated the MAPK pathway, which was abolished by the combination drugs. Our study provides a rationale for clinical testing of dual targeting FGFR and CCND1 with LY2874455 and abemaciclib in NSCLC patients who harbored FGF3/4/19/CCND1 amplification. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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