Fibroblast growth factor receptors in cancer: genetic alterations, diagnostics, therapeutic targets and mechanisms of resistance

Abstract

Fibroblast growth factor receptors (FGFRs) are aberrantly activated through single-nucleotide variants, gene fusions and copy number amplifications in 5–10% of all human cancers, although this frequency increases to 10–30% in urothelial carcinoma and intrahepatic cholangiocarcinoma. We begin this review by highlighting the diversity of FGFR genomic alterations identified in human cancers and the current challenges associated with the development of clinical-grade molecular diagnostic tests to accurately detect these alterations in the tissue and blood of patients. The past decade has seen significant advancements in the development of FGFR-targeted therapies, which include selective, non-selective and covalent small-molecule inhibitors, as well as monoclonal antibodies against the receptors. We describe the expanding landscape of anti-FGFR therapies that are being assessed in early phase and randomised controlled clinical trials, such as erdafitinib and pemigatinib, which are approved by the Food and Drug Administration for the treatment of FGFR3 -mutated urothelial carcinoma and FGFR2 -fusion cholangiocarcinoma, respectively. However, despite initial sensitivity to FGFR inhibition, acquired drug resistance leading to cancer progression develops in most patients. This phenomenon underscores the need to clearly delineate tumour-intrinsic and tumour-extrinsic mechanisms of resistance to facilitate the development of second-generation FGFR inhibitors and novel treatment strategies beyond progression on targeted therapy.

Erdafitinib treatment in Brazilian patients with metastatic urothelial carcinoma (mUC): real-world evidence from an Expanded Access Program

“…In this context, to evaluate FGFR2/3 alterations in tumor tissue there is a preference for RNA-based techniques. 15 In our study, to assess the FGFR2/3 alterations, we used the same methodology applied in the BLC2001 trial, the RNA-based technique RT–PCR in tumor samples.…”

Fibroblast Growth Factor Receptor (FGFR) Signaling in GIST and Soft Tissue Sarcomas

“…The evidence for the clinical impact of FGFR inhibition in STS patients is currently very limited and for the most part still under investigation. It is also important to consider that response rates seen with FGFR inhibitor therapy in multiple cancer histologies (around 20–40%) are significantly below those observed for patients with other oncogenic fusions such as those involving ALK , ROS1 , and NTRK (around 60–70%) [ 98 ]. Moreover, with the exception of cases of PMT and associated TIO, there have been virtually no reports of STS patients treated with selective FGFR inhibitors with sustained tumor response.…”

Fibroblast Growth Factor Inhibitors for Treating Locally Advanced/Metastatic Bladder Urothelial Carcinomas via Dual Targeting of Tumor-Specific Oncogenic Signaling and the Tumor Immune Microenvironment

“…The canonical and endocrine FGFs exert their biological effects by signaling via FGFR1-4, which consists of three extracellular (EC) domains, a transmembrane (TM) domain, and two intracellular tyrosine kinase (TK) domains (TK1 and TK2) [4,5,8,15,17,[22][23][24][25][26] (Figure 1). The EC region encompasses three immunoglobulin-like subdomains (I, II, and III) and an acid box, which is typically located between subdomains I and II, whereas the FGF ligand-binding site is located on subdomains II and III.…”

“…The TM region is made up of a single α-helix, and the IC tyrosine kinase domain exhibits the canonical bilobed architecture of the protein kinases. In conjunction with heparin sulfate proteoglycan (HSPG), the receptors bind FGF ligands, leading to receptor dimerization and autophosphorylation, and each specific phosphorylation site can bind and phosphorylate substrates to activate multiple signal transduction pathways (Figure 2) [4,5,8,11,13,[15][16][17][22][23][24][25][26]. Exquisitely precise fine-tuning of FGFR activity occurs via multiple steps of splicing and regulated expression, activity, and downstream signaling [11,13,16,17,23,[25][26][27].…”