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Targeted Therapies for Bladder Cancer and Beyond: Overview and Current Status of FGFR Inhibitors

Ignacio Duran, MD, PhD
Released: June 14, 2021

FGFR Signaling

FGF-FGFR and Erdafitinib

To understand why we should consider FGFR inhibitors both in second or subsequent lines of therapy in patients with bladder cancer and genetic alterations in those receptors, I think it is important to understand the physiology of FGF-FGFR and the role of FGFR as a carcinogenesis factor.

FGF and FGFR: Background

FGF was first isolated in the 1970s.[5,6] The FGF family includes 22 members divided into 7 subfamilies and, based on the mechanism of action, FGFs are classified into 3 groups: canonical FGF, endocrine FGF and the intracellular FGF.[7] The canonical and endocrine groups are most relevant for this discussion because they produce their biological actions by signaling through FGFRs 1-4.

FGF Receptor

FGFR is expressed on the cell membrane and comprises an extracellular domain with 3 immunoglobulin (Ig)-like domains—I, II, and III—a transmembrane domain, and inside the cell, there are 2 intracellular tyrosine kinase domains, TK1 and TK2.[8,9] 

FGF-FGFR Interaction

The FGFR tyrosine kinase domains bind ATP and phosphorylate tyrosine residues.[10] Binding of the FGF ligand and essential proteoglycan cofactors, heparin and heparan sulphate, leads to dimerization of the receptor and activation of 4 major intracellular signaling pathways: STATs, Ras-Raf-MAPK, PI3K-AKT, and PLCγ.[7,11]

Activation of these pathways results in key cell behaviors such as proliferation, differentiation, survival, migration, and angiogenesis.[7,12]

The family of endocrine FGFs regulate critical activities such as lipid metabolism, bile acid metabolism, and phosphate and vitamin D levels in the serum.[7,13,14]

FGFR and Cancer

The oncogenic function of FGF-FGFR signaling in directing cancer cell survival, proliferation, migration, and invasion occurs via upregulation of FGF, FGFR genetic modifications, angiogenesis and immune evasion within the tumor microenvironment. In an analysis of 4853 solid tumors, 7.1% of cancers had FGFR aberrations such as gene amplification (66%), mutations (26%), and rearrangements (8%). Alterations were most frequently found in FGFR1 (49%), followed by FGFR3 (26%), and FGFR2 (19%). FGFR4 was altered in only 7% of cases.[14,15] 

Ligand-Independent Mechanisms of FGFR Activation

The FGF-FGFR interaction drives cancer cell proliferation by different mechanisms that can be explained by 3 key ligand-independent mechanisms of FGFR activation. When there is an abnormality in FGFR, FGFR function is abnormal, leading to uncontrolled cell growth, and this is how FGF and FGFR are going to be critical in tumorigenesis.

FGFR gene amplification leads to protein overexpression, resulting in increased receptor accumulation that will lead to activation of the downstream signaling pathways.

Activating mutations in the receptor can result in receptor dimerization even in the absence of a ligand. This process is referred to as constitutive kinase domain activation.

Another interesting ligand-independent mechanism is called oncogenic fusion that results from chromosomal translocations, shown in “C.” Fusion with genes that encode other proteins can increase the receptor dimerization or will lead to receptor hyperactivation.[16]

FGFR Somatic Mutation Frequencies and Locations

Regarding the frequency of the receptor’s somatic mutations and where those mutations occur, FGFR2 and FGFR3 are the receptors that have the higher number of mutations. Those mutations occur predominantly in the ligand binding and the transmembrane domains. Mutations in FGFR1 and FGFR4 are not frequently reported.[16]

FGFR Gene Fusions

This slide shows how different gene fusions of FGFR can lead to variable expression of some fusion proteins, containing a transcription factor and tyrosine kinases that can induce ligand-independent receptor dimerization and oncogenic effects.[14] One of the most common is FGFR3-TACC3. It is present in UC and other tumors and can phosphorylate phosphopeptide PIN4 while promoting tumor growth and triggering MAPK-ERK and JAK-STAT signaling pathways.[17]

FGFR: A Potential Target in Multiple Tumor Types

Our understanding of FGF-FGFR biology revealed how it can be a potential target in multiple tumor types. Abnormalities in FGFR, including amplifications, mutations, and fusions are found in many different tumor types. Although the focus of this review is UC since FGFR alterations are relatively common in this setting and FGFR-targeted therapy was first approved in this disease, there are different frequencies, percentage of fusions, mutations, and amplifications in different genes of this family across a variety of cancers.[18]

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