Frontiers in Pharmacology (Jun 2022)

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

  • Dongcheng Liu,
  • Dongcheng Liu,
  • Dongcheng Liu,
  • 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

DOI
https://doi.org/10.3389/fphar.2022.918317
Journal volume & issue
Vol. 13

Abstract

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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.

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