Molecular Targeting of the Fibroblast Growth Factor Receptor Pathway across Various Cancers

International Journal of Molecular Sciences · 6 authors, 1 centre

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TL;DR

This narrative review summarizes the role of FGFR aberrations in cancer and the development of FGFR-targeting therapies. It concludes that FGFR inhibitors have shown efficacy in tumors with FGFR alterations but face challenges like patient selection, acquired resistance, and toxicity management.

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This narrative review discusses the FGFR signaling pathway and its dysregulation through gene amplifications, mutations, and fusions in various cancers. It summarizes the landscape of FGFR-targeting therapies, including small-molecule tyrosine kinase inhibitors, ligand traps, monoclonal antibodies, and antibody–drug conjugates. The authors note that four FDA-approved FGFR inhibitors exist for specific cancers. The review highlights that FGFR inhibitors have demonstrated efficacy in clinical trials for patients with hematological conditions, intrahepatic cholangiocarcinoma, lung cancers, and urothelial carcinomas. Key limitations and challenges include difficulties in patient selection and molecular detection of FGFR alterations, the development of acquired resistance due to secondary mutations, and the management of toxicities. The review suggests future directions, such as combination therapies with mTOR, EGFR, or MAPK pathway inhibitors to overcome resistance, and further investigation into immunotherapy combinations and novel agent development.

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narrative_review

SPECIALTY

oncology

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ORIGINAL PAPER

PMC10815772

Molecular Targeting of the Fibroblast Growth Factor Receptor Pathway across Various Cancers

International Journal of Molecular Sciences

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ABSTRACT

Abstract Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases that are involved in the regulation of cell proliferation, survival, and development. FGFR alterations including amplifications, fusions, rearrangements, and mutations can result in the downstream activation of tyrosine kinases, leading to tumor development. Targeting these FGFR alterations has shown to be effective in treating cholangiocarcinoma, urothelial carcinoma, and myeloid/lymphoid neoplasms, and there are currently four FGFR inhibitors approved by the Food and Drug Administration (FDA). There have been developments in multiple agents targeting the FGFR pathway, including selective FGFR inhibitors, ligand traps, monoclonal antibodies, and antibody–drug conjugates. However, most of these agents have variable and low responses, with some intolerable toxicities and acquired resistances. This review will summarize previous clinical experiences and current developments in agents targeting the FGFR pathway, and will also discuss future directions for FGFR-targeting agents. Keywords: FGF, FGFR, fibroblast growth factor receptor, fibroblast growth factor, targeted therapy, genomic profiling, personalized medicine

CITATION EXPORT

Khine S Shan, Shivani Dalal, Nyein Nyein Thaw Dar et al.. Molecular Targeting of the Fibroblast Growth Factor Receptor Pathway across Various Cancers. International Journal of Molecular Sciences. (2024). https://doi.org/10.3390/ijms25020849

AUTHORS

6 · 1 CENTRES

Khine S Shan, Shivani Dalal, Nyein Nyein Thaw Dar, Omani McLish, Matthew Salzberg, Brian A Pico

1Memorial Health Care, Division of Hematology and Oncology, Pembroke Pines, FL 33028, USA; [email protected] (S.D.); [email protected] (N.N.T.D.); [email protected] (O.M.); [email protected] (M.S.);