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

• DOI: 10.3389/fphar.2022.918317
• Publication Date: 2022-06-23T07:30:18Z
• 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 ...; Wenfeng Fang; Lingwei Wang
• Keywords: Pharmacology; 03 medical and health sciences; 0302 clinical medicine; FGF3/4/19/CCND1 amplification; LY2874455; abemaciclib; Therapeutics. Pharmacology; RM1-950; NSCLC; gefitinib resistance; 3. Good health

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 these amplifications TKI-resistant NSCLC remains uncovered. Here, we generated model lines PC-9 and HCC827. Upregulation strongly promoted proliferation gefitinib cells. To find out potential therapeutic strategies, screened combination inhibitors against FGF/FGFR signaling pathway CCND1/CDK4 revealed that combined LY2874455 abemaciclib exhibited most effective inhibition vitro vivo . Mechanistically, FGFs/CCND1 activated MAPK pathway, which abolished by drugs. Our study provides a rationale for clinical testing dual targeting FGFR CCND1 harbored amplification.