1. LY2874455 and Abemaciclib Reverse FGF3/4/19/CCND1 Amplification Mediated Gefitinib Resistance in NSCLC.
- Author
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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, and Wang, Lingwei
- Subjects
NON-small-cell lung carcinoma ,PROTEIN-tyrosine kinase inhibitors ,GEFITINIB - Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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