FGFR-targeted therapeutics: clinical activity, mechanisms of resistance and new directions.


Journal

Nature reviews. Clinical oncology
ISSN: 1759-4782
Titre abrégé: Nat Rev Clin Oncol
Pays: England
ID NLM: 101500077

Informations de publication

Date de publication:
29 Feb 2024
Historique:
accepted: 06 02 2024
medline: 1 3 2024
pubmed: 1 3 2024
entrez: 29 2 2024
Statut: aheadofprint

Résumé

Fibroblast growth factor (FGF) signalling via FGF receptors (FGFR1-4) orchestrates fetal development and contributes to tissue and whole-body homeostasis, but can also promote tumorigenesis. Various agents, including pan-FGFR inhibitors (erdafitinib and futibatinib), FGFR1/2/3 inhibitors (infigratinib and pemigatinib), as well as a range of more-specific agents, have been developed and several have entered clinical use. Erdafitinib is approved for patients with urothelial carcinoma harbouring FGFR2/3 alterations, and futibatinib and pemigatinib are approved for patients with cholangiocarcinoma harbouring FGFR2 fusions and/or rearrangements. Clinical benefit from these agents is in part limited by hyperphosphataemia owing to off-target inhibition of FGFR1 as well as the emergence of resistance mutations in FGFR genes, activation of bypass signalling pathways, concurrent TP53 alterations and possibly epithelial-mesenchymal transition-related isoform switching. The next generation of small-molecule inhibitors, such as lirafugratinib and LOXO-435, and the FGFR2-specific antibody bemarituzumab are expected to have a reduced risk of hyperphosphataemia and the ability to overcome certain resistance mutations. In this Review, we describe the development and current clinical role of FGFR inhibitors and provide perspective on future research directions including expansion of the therapeutic indications for use of FGFR inhibitors, combination of these agents with immune-checkpoint inhibitors and the application of novel technologies, such as artificial intelligence.

Identifiants

pubmed: 38424198
doi: 10.1038/s41571-024-00869-z
pii: 10.1038/s41571-024-00869-z
doi:

Types de publication

Journal Article Review

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

© 2024. Springer Nature Limited.

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Auteurs

Masuko Katoh (M)

M & M Precision Medicine, Tokyo, Japan.

Yohann Loriot (Y)

Drug Development Department (DITEP), Institut Gustave Roussy, Université Paris-Saclay, Villejuif, France.
INSERM U981, Institut Gustave Roussy, Université Paris-Saclay, Villejuif, France.

Giovanni Brandi (G)

Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.

Simona Tavolari (S)

Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.

Zev A Wainberg (ZA)

Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA.

Masaru Katoh (M)

M & M Precision Medicine, Tokyo, Japan. mkatoh-kkr@umin.ac.jp.
Department of Omics Network, National Cancer Center, Tokyo, Japan. mkatoh-kkr@umin.ac.jp.

Classifications MeSH