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

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:10.3389/fphar.2022.918317

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

Front Pharmacol. 2022 Jun 23:13:918317. doi: 10.3389/fphar.2022.918317. eCollection 2022.

Authors

Dongcheng Liu^{1

2

3

4}, Hongguang Liu⁵, Jiadi Gan⁶, Shinuan Zeng³, Fuhua Zhong³, Bin Zhang³, Zhe Zhang³, Siyu Zhang³, Lu Jiang³, Guangsuo Wang⁷, Yixin Chen⁸, Feng-Ming Spring Kong⁹, Wenfeng Fang⁶, Lingwei Wang¹

Affiliations

¹ Department of Respiratory and Critical Care Medicine, Shenzhen Institute of Respiratory Diseases, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen People's Hospital, Shenzhen, China.
² Shenzhen Aier Eye Hospital Affiliated to Jinan University, Shenzhen, China.
³ Department of Clinical Medical Research Center, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen People's Hospital, Shenzhen, China.
⁴ Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou, China.
⁵ Department of Laboratory Medicine, Huazhong University of Science and Technology Union Shenzhen Hospital (Nanshan Hospital), Shenzhen, China.
⁶ Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
⁷ Department of Thoracic Surgery, The First Affiliated Hospital of Southern University of Sciences and Technology, Shenzhen People's Hospital, Shenzhen, China.
⁸ Department of Oncology, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen People's Hospital, Shenzhen, China.
⁹ Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.

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.

Keywords: FGF3/4/19/CCND1 amplification; LY2874455; NSCLC; abemaciclib; gefitinib resistance.