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Updated: Mar 12, 2026

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
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Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells

Published on: October 27, 2020

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FGFR signaling maintains a drug persistent cell population following epithelial-mesenchymal transition

Wells S Brown1, Saeed Salehin Akhand1, Michael K Wendt1

  • 1Purdue University Center for Cancer Research, Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, USA.

Oncotarget
|November 9, 2016
PubMed

Insights

Drug resistance in breast cancer involves epithelial-mesenchymal transition (EMT). Targeting fibroblast growth factor receptor 1 (FGFR1) with inhibitors can overcome resistance when combined with Her2-targeted therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Drug resistance is a major challenge in cancer therapy.
  • Epithelial-mesenchymal transition (EMT) is an emerging mechanism of drug resistance.
  • Mechanisms underlying EMT-mediated drug resistance are not fully understood.

Purpose of the Study:

  • To investigate the mechanisms of EMT-induced drug resistance in Her2-positive breast cancer.
  • To identify potential therapeutic targets for overcoming drug resistance.
  • To evaluate the efficacy of combined Her2-targeted and FGFR-targeted therapies.

Main Methods:

  • Long-term treatment of Her2-transformed breast cancer cells with Lapatinib or TGF-β.
  • Analysis of EMT phenotypes and mesenchymal-epithelial transition (MET).
  • Gene expression profiling using Nanostring cancer progression panel.
  • Investigation of FGF:Erk1/2 signaling pathway and Twist stabilization.
  • Testing efficacy of covalent FGFR inhibitors.

Main Results:

  • Both Lapatinib and TGF-β induced EMT phenotypes.
  • TGF-β induced cells could undergo MET, while Lapatinib-induced cells did not.
  • Mesenchymal cells were selected for during subsequent Lapatinib treatment, leading to drug resistance.
  • Upregulation of fibroblast growth factor receptor 1 (FGFR1) and FGF2 was observed in resistant cells.
  • FGF:Erk1/2 signaling stabilized Twist, maintaining the mesenchymal and drug-resistant phenotype.
  • Covalent FGFR inhibitors effectively eliminated Lapatinib-resistant cells.

Conclusions:

  • Targeting FGFR1 in combination with Her2-targeted therapies can overcome drug resistance in Her2-positive breast cancer.
  • The FGF:Erk1/2 signaling pathway plays a crucial role in maintaining EMT and drug resistance.
  • FGFR inhibitors represent a promising therapeutic strategy for resistant breast cancer subtypes.
Keywords:
EMTFGFRHer2 resistancebreast cancercovalent kinase inhibitor

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