Fibroblast growth factor receptor fusions in cancer: opportunities and challenges

Abstract

Fibroblast growth factors (FGFs) and their receptors (FGFRs) play critical roles in many biological processes and developmental functions. Chromosomal translocation of FGFRs result in the formation of chimeric FGFR fusion proteins, which often cause aberrant signaling leading to the development and progression of human cancer. Due to the high recurrence rate and carcinogenicity, oncogenic FGFR gene fusions have been identified as promising therapeutic targets. Erdafitinib and pemigatinib, two FGFR selective inhibitors targeting FGFR fusions, have been approved by the U.S. Food and Drug Administration (FDA) to treat patients with urothelial cancer and cholangiocarcinoma, respectively. Futibatinib, a third-generation FGFR inhibitor, is under phase III clinical trials in patients with FGFR gene rearrangements. Herein, we review the current understanding of the FGF/FGFRs system and the oncogenic effect of FGFR fusions, summarize promising inhibitors under clinical development for patients with FGFR fusions, and highlight the challenges in this field.

Keywords: Cancer; Chromosomal translocation; Fibroblast growth factor receptors; Fusion proteins; Inhibitors.

Fig. 1

FGF–FGFR-HS system. A 18 functional mammalian FGFs sorted into six subfamilies. Each founding members are colored in orange. B Left: paracrine FGFs bind to the D2-D3 domains of FGFRs and HS to form 2:2:2 FGF-FGFR-HS complex (PDB: 1FQ9). Right: Endocrine FGF-FGFR-Klotho complex PDB ID: 5 W21). Alternatively-spliced D3 domain of FGFR is highlighted in purple

Fig. 2

FGFR signaling in cancers. FGF, HSPG, and FGFR form 2:2:2 ternary complex, followed by receptor dimerization and kinase transphosphorylation. FGFR downstream adaptor protein FRS2 interacts with SHP2 and GRB2 complex, leading to subsequent activation of PI3K-AKT and RAS-MEK-ERK signaling pathways. Another FGFR substrate, PLC-g, binds to phosphotyrosine and hydrolyzes PIP2 to generate IP3 and DAG, which in turn activate PKC and MAPK pathway, resulting in cell migration, proliferation, and differentiation. Depending on the cellular context, FGFRs have the capability to activate the JAK-STAT3 signalling pathway. Aberrant FGFR signaling may be induced by (i) increased expression of FGFs (ligand-dependent), or (ii) FGFR alteration, including mutation, amplification or translocation (ligand-independent)

Fig. 3

FGFR autoinhibition mechanisms. A Schematic representations of FGFR autoinhibition modes consisting of acid box regulation, molecular brake, DFG latch, and the repulsion between enzyme and substrate kinases B overall view of the asymmetric FGFR kinase A-loop transphosphorylation complex (PDB: 6PNX). Enzyme- and substrate-acting FGFR kinases are colored in green, blue and wheat, respectively. C FGFR3 K659 and R669 form enzyme-substrate electrostatic clash. Sequence alignment of the kinase domains of FGFR1–4 shows the conservation of autoinhibition mechanism. D Hydrogen bonding pattern of the autoinhibitory molecular brake in FGFR1 (left, PDB ID: 1fgk) and disengaged brake (right, PDB ID: 3gqi). The dashed lines denote hydrogen bonds

Fig. 4

FGFR fusions. A Schematic representations of FGFR type I/II fusions. Fusions of FGFR with genes that encode other signaling proteins at N- terminal (type I) or C- terminal (type II) result in release of autoinhibition state and followed by aberrant kinase activation. B Potential oncogenic mechanisms of FGFR fusions. Left: fusions produce elevated oncogenic signaling through promoter exchange and FGFR overexpression. Middle: ligand-independent FGFR oligomerization lead to constitutively activation of FGFR kinase mediated by the PPIs through the oligomerization domain (OD) within the fusion partners. Right: FGFR fusion oncoproteins may undergo a higher-order assembly to produce membraneless cytoplasmic protein granules that promote local RAS activation and induce MAPK signaling activation in cancer. TM, transmembrane region; TK, tyrosine kinase domain

Fig. 5

FGFR inhibitors. A Chemical structures of selected FGFR inhibitors and PROTAC. The hinge binding region and FGFR hydrophobic pocket binding group are highlighted. B Structures of second- and third-generation drug-FGFR complexes, including erdafitinib (5ew8), infigratinib (3tt0), debio-1347 (5b7v), and TAS120 (6mzw) in complex with FGFR1 kinase domain