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BRIEF RESEARCH REPORT article

Front. Pharmacol.
Sec. Pharmacology of Anti-Cancer Drugs
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1459820
This article is part of the Research Topic Innovative Approaches to Overcome Resistance and Toxicities of Anti-Cancer Drugs View all 18 articles

Overcoming drug resistance of cancer cells by targeting the FGF1/FGFR1 axis with honokiol or FGF ligand trap

Provisionally accepted
Jakub Szymczyk Jakub Szymczyk 1Martyna Sochacka Martyna Sochacka 2*Martyna Biadun Martyna Biadun 1*Katarzyna D. Sluzalska Katarzyna D. Sluzalska 1Danuta Witkowska Danuta Witkowska 3Malgorzata Zakrzewska Malgorzata Zakrzewska 1*
  • 1 Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Wrocław, Silesian, Poland
  • 2 Department of Protein Biotechnology, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland
  • 3 Institute of Health Sciences, University of Opole, Opole, Opole, Poland

The final, formatted version of the article will be published soon.

    Background: Chemoresistance of cancer cells, resulting from various mechanisms, is a significant obstacle to the effectiveness of modern cancer therapies. Targeting fibroblast growth factors (FGFs) and their receptors (FGFRs) is becoming crucial, as their high activity significantly contributes to cancer development and progression by driving cell proliferation and activating signaling pathways that enhance drug resistance.Methods: We investigated the potential of honokiol and FGF ligand trap in blocking the FGF1/FGFR1 axis to counteract drug resistance. Using PEAQ-ITC, we verified direct interaction of honokiol with the FGFR1 kinase domain. We then demonstrated the effect of FGF1/FGFR1 inhibition on taltobulin resistance in cells expressing FGFR1. Finally, we generated drug-resistant clones by prolonged exposure of cells with negligible FGFR levels to taltobulin alone, taltobulin and honokiol, or taltobulin and FGF ligand trap.We demonstrated for the first time a direct interaction of honokiol with the FGFR1 kinase domain, resulting in inhibition of downstream signaling pathways. We revealed that both honokiol and FGF ligand trap prevent FGF1-dependent protection against taltobulin in cancer cells expressing FGFR1. In addition, we showed that cells obtained by long-term exposure to taltobulin are resistant to both taltobulin and other microtubule-targeting drugs, and exhibit elevated levels of FGFR1 and cyclin D. We also found that the presence of FGF-ligand trap prevents the development of long-term resistance to taltobulin.Our results shed light on how blocking the FGF1/FGFR1 axis by honokiol and FGF ligand trap could help develop more effective cancer therapies, potentially preventing the emergence of drug-resistant relapses.

    Keywords: FGF1, FGFR1, Drug Resistance, honokiol, Ligand Trap, Cancer, anti-cancer drugs, taltobulin

    Received: 04 Jul 2024; Accepted: 21 Aug 2024.

    Copyright: © 2024 Szymczyk, Sochacka, Biadun, Sluzalska, Witkowska and Zakrzewska. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Martyna Sochacka, Department of Protein Biotechnology, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland
    Martyna Biadun, Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Wrocław, Silesian, Poland
    Malgorzata Zakrzewska, Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Wrocław, Silesian, Poland

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.