Autor: |
Dongcheng Liu, Hongguang Liu, Jiadi Gan, Shinuan Zeng, Fuhua Zhong, Bin Zhang, Zhe Zhang, Siyu Zhang, Lu Jiang, Guangsuo Wang, Yixin Chen, Feng-Ming Spring Kong, Wenfeng Fang, Lingwei Wang |
Jazyk: |
angličtina |
Rok vydání: |
2022 |
Předmět: |
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Zdroj: |
Frontiers in Pharmacology, Vol 13 (2022) |
Druh dokumentu: |
article |
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: |
Directory of Open Access Journals |
Externí odkaz: |
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