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Updated: Jul 1, 2025
Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
Published on: December 9, 2015
FGFR-targeted therapeutics: clinical activity, mechanisms of resistance and new directions
Masuko Katoh1, Yohann Loriot2,3, Giovanni Brandi4,5
1M & M Precision Medicine, Tokyo, Japan.
Abstract:
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.
Insights
Fibroblast growth factor receptor (FGFR) inhibitors are crucial in cancer therapy but face challenges like side effects and resistance. Next-generation FGFR inhibitors aim to improve efficacy and reduce toxicity for better patient outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Drug Development
Background:
- Fibroblast growth factor (FGF) signaling through FGF receptors (FGFR1-4) is vital for development and homeostasis, but aberrant signaling drives tumorigenesis.
- Current FGFR inhibitors (erdafitinib, futibatinib, infigratinib, pemigatinib) are approved for specific cancers like urothelial carcinoma and cholangiocarcinoma.
- Clinical benefits are limited by hyperphosphatemia (off-target FGFR1 inhibition) and acquired resistance mechanisms (mutations, bypass pathways, TP53 alterations).
Purpose of the Study:
- To review the development and current clinical applications of FGFR inhibitors in cancer treatment.
- To discuss emerging resistance mechanisms and limitations of existing therapies.
- To provide perspectives on future research directions for optimizing FGFR inhibitor therapy.
Main Methods:
- Review of existing literature on FGFR inhibitors, their clinical trials, and mechanisms of action.
- Analysis of approved FGFR inhibitors and their therapeutic indications.
- Discussion of emerging next-generation inhibitors and novel therapeutic strategies.
Main Results:
- Several FGFR inhibitors have gained regulatory approval for specific cancer types.
- Hyperphosphatemia and resistance mutations are significant clinical challenges.
- Next-generation inhibitors (lirafugratinib, LOXO-435) and antibody-based therapies (bemarituzumab) show promise in overcoming these limitations.
Conclusions:
- FGFR inhibitors represent a significant advancement in targeted cancer therapy.
- Addressing resistance and off-target toxicities is crucial for improving therapeutic efficacy.
- Future research should focus on novel inhibitors, combination therapies (e.g., with immune checkpoint inhibitors), and expanded indications.
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