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.

Fig. 1. Cancer types that harbour alterations in FGFR.

FGFR alterations, including single-nucleotide variants (SNVs), fusions and copy number amplifications (CNAs) have been frequently detected in multiple types of human cancer at varying percentages.

Fig. 2. Current clinical landscape of FGFR inhibitors.

Numerous FGFR inhibitors are currently being assessed in preclinical, Phase 1, Phase 2 and Phase 3 clinical trials. This figure does not include trials assessing FGFR inhibitors in combination with other therapeutic strategies. Erdafitinib and pemigatinib are currently the only approved inhibitors for use in the treatment of patients with FGFR-altered urothelial cancers and cholangiocarcinoma, respectively.

Fig. 3. FGFR resistance mutations.

Summary of mutations in FGFR1–4 that have been shown to confer resistance to FGFR inhibitors. Ig immunoglobulin domain, TK tyrosine kinase.