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The FGF/FGFR signalling mediated anti-cancer drug resistance and therapeutic intervention

Subhasmita Mahapatra¹, Nisha Amarnath Jonniya¹, Suman Koirala¹

¹Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, Madhya Pradesh, India.

Journal of Biomolecular Structure & Dynamics

|March 30, 2023

Abstract:

Fibroblast Growth Factor (FGF) ligands and their receptors are crucial factors driving chemoresistance in several malignancies, challenging the efficacy of currently available anti-cancer drugs. The Fibroblast growth factor/receptor (FGF/FGFR) signalling malfunctions in tumor cells, resulting in a range of molecular pathways that may impact its drug effectiveness. Deregulation of cell signalling is critical since it can enhance tumor growth and metastasis. Overexpression and mutation of FGF/FGFR induce regulatory changes in the signalling pathways. Chromosomal translocation facilitating FGFR fusion production aggravates drug resistance. Apoptosis is inhibited by FGFR-activated signalling pathways, reducing multiple anti-cancer medications' destructive impacts. Angiogenesis and epithelial-mesenchymal transition (EMT) are facilitated by FGFRs-dependent signalling, which correlates with drug resistance and enhances metastasis. Further, lysosome-mediated drug sequestration is another prominent method of resistance. Inhibition of FGF/FGFR by following a plethora of therapeutic approaches such as covalent and multitarget inhibitors, ligand traps, monoclonal antibodies, recombinant FGFs, combination therapy, and targeting lysosomes and micro RNAs would be helpful. As a result, FGF/FGFR suppression treatment options are evolving nowadays. To increase positive impacts, the processes underpinning the FGF/FGFR axis' role in developing drug resistance need to be clarified, emphasizing the need for more studies to develop novel therapeutic options to address this significant problem. Communicated by Ramaswamy H. Sarma.

Insights

Fibroblast Growth Factor (FGF) and its receptor (FGFR) signaling pathways drive chemoresistance in cancers. Targeting the FGF/FGFR axis offers promising strategies to overcome drug resistance and improve anti-cancer therapy efficacy.

Area of Science:

Oncology
Molecular Biology
Pharmacology

Background:

Fibroblast Growth Factor (FGF) and its receptor (FGFR) signaling pathways are implicated in cancer development and progression.
Dysregulation of FGF/FGFR signaling, including overexpression, mutation, and fusion, contributes to chemoresistance in various malignancies.
This axis impacts critical cellular processes such as cell signaling, apoptosis, angiogenesis, and epithelial-mesenchymal transition (EMT), influencing drug effectiveness.

Purpose of the Study:

To elucidate the multifaceted role of the FGF/FGFR axis in mediating chemoresistance across different cancers.
To review current and emerging therapeutic strategies targeting the FGF/FGFR pathway for overcoming drug resistance.
To highlight the need for further research into FGF/FGFR-driven resistance mechanisms and novel therapeutic interventions.

Main Methods:

Comprehensive literature review of studies investigating FGF/FGFR signaling in cancer drug resistance.
Analysis of molecular mechanisms by which FGF/FGFR activation confers resistance, including pathway deregulation, apoptosis inhibition, angiogenesis, and EMT.
Evaluation of therapeutic approaches targeting the FGF/FGFR axis, such as inhibitors, ligand traps, antibodies, and combination therapies.

Main Results:

FGF/FGFR signaling promotes tumor growth, metastasis, and resistance to multiple anti-cancer drugs through various molecular mechanisms.
Mechanisms include deregulation of signaling pathways, inhibition of apoptosis, promotion of angiogenesis and EMT, and lysosome-mediated drug sequestration.
Various therapeutic strategies targeting FGF/FGFR are under investigation, showing potential to overcome drug resistance.

Conclusions:

The FGF/FGFR axis is a critical determinant of chemoresistance in cancer, necessitating targeted therapeutic interventions.
Emerging strategies focusing on FGF/FGFR suppression, including inhibitors and combination therapies, hold promise for improving anti-cancer treatment outcomes.
Further research is essential to fully understand FGF/FGFR-mediated resistance and develop more effective therapies.

Read full analysis

Keywords:

FGF/FGFR signalling anti-cancer drugs chemoresistance therapeutic approaches

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