J Korean Med Sci.  2024 Nov;39(43):e320. 10.3346/jkms.2024.39.e320.

FGFR Inhibitors in Urothelial Cancer: From Scientific Rationale to Clinical Development

• Kwon WA

• KMID: 2561431
• DOI: http://doi.org/10.3346/jkms.2024.39.e320

Abstract

In the past decade, the treatment of metastatic urothelial cancer (mUC), including bladder cancer (BC), has transformed significantly with the introduction of diverse therapies, such as immune checkpoint inhibitors, targeted therapies, and antibody-drug conjugates. This change is partly due to advancements in genomic understanding, particularly nextgeneration sequencing, which has identified numerous mutations in UC. Among these therapies, erdafitinib, a pan-fibroblast growth factor receptor (FGFR) inhibitor for specific FGFR2 and FGFR3 alterations, is the only targeted therapy approved till now. In 2019, erdafitinib became pivotal for the treatment of mUC, particularly in patients with specific FGFR alterations. Recent studies have highlighted the benefits of combining erdafitinib with immunotherapy, thereby broadening the treatment options. Ongoing investigations exist on its use in non-muscle-invasive BC and in combination with drugs such as enfortumab vedotin in mUC. Other FGFR-targeted agents are under development; however, overcoming FGFR resistance and ensuring the safety of combination therapies remain major hurdles. FGFR3 mutations are particularly prevalent in BC, a heterogeneous form of UC, and account for a considerable proportion of new cancer diagnoses annually. Approximately half of these cancers have FGFR3 mutations, with gene rearrangements being a common feature. These FGFR3 genomic alterations often occur independently of mutations in other BC oncogenes, such as TP53 and RB1. This review emphasizes the importance of FGFR inhibition in UC and the optimization of its use in clinical practice. Moreover, it underscores the ongoing efforts to evaluate combination strategies and early treatment testing to enhance the effectiveness of targeted therapies for UC.

Keyword

Bladder Cancer; Erdafitinib; Fibroblast Growth Factor Receptor; Precision Medicine; Tyrosine Kinase Inhibitors; Urothelial Cancer

Figure

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  Fig. 1 Summary of the primary functions of FGF/FGFR signaling in various physiological and pathological contexts is as follows: FGF/FGFR signaling is crucial in the development of nearly all organs, including the lungs, heart, urinary system, brain, skeleton, muscles, and skin/appendages, along with angiogenesis and lymphangiogenesis. FGFs/FGFRs significantly influence tissue repair, regeneration, and inflammatory responses. Endocrine FGFs are vital in metabolism, affecting the kidneys, liver, brain, intestines, and adipose tissue. Disruptions in FGF/FGFR signaling can result in a variety of diseases, such as genetic disorders, cancer, COPD, and CKD. Created with BioRender.com.FGF = fibroblast growth factor, FGFR = fibroblast growth factor receptor, CKD = chronic kidney disease, COPD = chronic obstructive pulmonary disease.

• 

  Fig. 2 The classical FGF/FGFR pathways involve several key steps and molecules. When appropriate growth factors bind to receptors, they induce conformational changes in FGFRs, leading to their dimerization and activation. Once activated, FGFRs phosphorylate FRS2α, which then binds to the SH2 domain-containing adaptor protein Grb2. Grb2 connects to SOS, GAB1, and Cbl through its SH3 domain, initiating the activation of the Ras/Raf/MAPK pathways, including ERK MAPK, p38 MAPK, and JNK MAPK. Additionally, activated FGFRs stimulate phosphatidylinositol-3 kinase and STAT pathways. FGFRs also recruit and phosphorylate PLCγ. Within the FGF synexpression group, SEF and XFLRT3, both transmembrane proteins, directly interact with FGFRs. SEF acts as a negative regulator by modulating the phosphorylation of the MAPK ERK cascade, while XFLRT3 enhances FGF/FGFR signaling by forming a complex with FGF receptors. Spry modulates FGF/FGFR signaling by acting at the level of Grb2 and/or Raf, and MKP3 negatively regulates this signaling by dephosphorylating activated ERK. Created with BioRender.com.FGF = fibroblast growth factor, FGFR = fibroblast growth factor receptor, MAPK = mitogen-activated protein kinase, PLCγ = phospholipase Cγ, FRS2α = fibroblast growth factor receptor substrate 2α, GAB1 = growth factor receptor-bound 2-associated binding protein 1, GRB2 = growth factor receptor-bound 2, PKC = protein kinase C, SOS = son of sevenless.

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