OncoTargets and Therapy (Nov 2019)

FGFR1 Induces Acquired Resistance Against Gefitinib By Activating AKT/mTOR Pathway In NSCLC

  • Zhang D,
  • Han L,
  • Du F,
  • Liu X,
  • Li J,
  • Wang H,
  • Song M,
  • Li Z,
  • Li G

Journal volume & issue
Vol. Volume 12
pp. 9809 – 9816

Abstract

Read online

Dan Zhang,1,2,* Li-li Han,3,* Fen Du,4,* Xiao-meng Liu,1 Jin Li,1 Hui-hui Wang,1 Ming-hui Song,1 Zeng Li,2 Guo-yin Li1 1College of Life Science and Agronomy, Zhoukou Normal University, Zhoukou, Henan, People’s Republic of China; 2Department of Oncology, Hanzhong 3201 Hospital Affiliated to Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 3Department of Respiratory, Zhoukou Central Hospital, Zhoukou, Henan, People’s Republic of China; 4Department of Nursing, Hanzhong Vocational Technical College, Hanzhong, Shaanxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guo-yin LiCollege of Life Science and Agronomy, Zhoukou Normal University, 6 Changle Wenchang Road, Zhoukou 466000, People’s Republic of ChinaEmail [email protected]: As an epidermal growth factor, receptor-tyrosine kinase inhibitor (EGFR-TKI), gefitinib demonstrates a good therapeutic effect in patients with EGFR-mutant non-small-cell lung cancer (NSCLC). However, an overwhelming majority of these patients inevitably develop resistance against gefitinib. Unfortunately, the mechanism underlying this phenomenon is still not fully understood. Here we aim to reveal the mechanism of gefitinib resistance in NSCLC induced by FGFR1.Materials and methods: We used high-throughput sequencing to compare the mRNA expression profiles of PC9 and PC9-GR (gefitinib-resistant) cells. The clinical significance of fibroblast growth factor receptor 1 (FGFR1) in NSCLC was also investigated using immunohistochemistry and Kaplan-Meier survival analysis. Finally, the in vitro molecular mechanisms were analyzed using confocal laser microscopy, Western blotting, transwell assay, colony formation assay, CCK-8 assay, and apoptosis assay.Results: We observed that FGFR1 was highly expressed in NSCLC tissues and was closely associated with poor prognosis. Cytological experiments showed that FGFR1 promoted the proliferation and migration of PC9-GR cells and mediated their resistance to gefitinib. Furthermore, studies aimed at unraveling this mechanism revealed that FGFR1 activated the AKT/mTOR signaling pathway. These findings show that the FGFR1/AKT/mTOR signaling pathway plays a vital role in acquired resistance against gefitinib in NSCLC.Conclusion: This work provides new evidence that FGFR1 functions as a key regulator of gefitinib resistance, thereby demonstrating its potential as a novel biomarker and therapeutic target for NSCLC.Keywords: fibroblast growth factor receptor 1, FGFR1, acquired resistance, gefitinib, non-small-cell lung cancer, NSCLC, AKT/mTOR pathway

Keywords