LY2874455 and Abemaciclib Reverse FGF3/4/19/CCND1 Amplification Mediated Gefitinib Resistance in NSCLC.

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.

• Authors: 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
• Journal: Frontiers in pharmacology (Front Pharmacol) Vol. 13 Pg. 918317 ( 2022) ISSN: 1663-9812 [Print] Switzerland
• PMID: 35814257 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Liu, Liu, Gan, Zeng, Zhong, Zhang, Zhang, Zhang, Jiang, Wang, Chen, Kong, Fang and Wang.