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Updated: Mar 6, 2026

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
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Akt Activation Mediates Acquired Resistance to Fibroblast Growth Factor Receptor Inhibitor BGJ398

Jharna Datta1, Senthilkumar Damodaran1,2, Hannah Parks1

  • 1Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.

Molecular Cancer Therapeutics
|March 4, 2017
PubMed

Insights

Acquired resistance to FGFR inhibitors in cancer can be overcome by targeting the Akt pathway. Inhibiting Akt signaling restored sensitivity to FGFR inhibitors in resistant cell lines, suggesting a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Resistance

Background:

  • Fibroblast Growth Factor Receptor (FGFR) signaling is activated in various cancers, including lung, bladder, and cholangiocarcinoma, through genetic alterations.
  • Novel FGFR inhibitors are under clinical investigation for solid tumors, necessitating an understanding of potential resistance mechanisms.
  • Acquired resistance to targeted therapies is a significant clinical challenge, prompting research into its underlying molecular basis.

Purpose of the Study:

  • To investigate the mechanisms of acquired resistance to FGFR inhibitors in cancer cell lines.
  • To identify potential therapeutic strategies to overcome FGFR inhibitor resistance.

Main Methods:

  • Utilized annotated cancer cell lines with activating FGFR mutations (FGFR1, FGFR2, FGFR3).
  • Exposed cell lines to chronic treatment with the selective FGFR inhibitor BGJ398 to induce resistance.
  • Employed viability assays, Reverse-Phase Protein Array (RPPA), and immunoblots to analyze molecular changes.
  • Tested the efficacy of combining FGFR inhibition with Akt pathway inhibition.

Main Results:

  • Developed resistant cell lines (DMS114, RT112) to chronic BGJ398 exposure.
  • Observed increased Akt phosphorylation (T308, S473) and downstream GSK3 phosphorylation (S9, S21) in resistant cells.
  • Demonstrated that co-treatment with an Akt inhibitor (GSK2141795) or siRNA restored sensitivity to BGJ398.

Conclusions:

  • The Akt signaling pathway plays a crucial role in mediating acquired resistance to FGFR inhibitors.
  • Combining FGFR inhibitors with Akt pathway inhibitors represents a promising therapeutic approach to overcome resistance in FGFR-driven cancers.

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