Fibroblast growth factor receptors as treatment targets in clinical oncology

FGFRs are receptor tyrosine kinases with a role in several biological processes, such as the regulation of development and tissue repair. However, alterations in FGFRs 1–4, such as amplifications, fusions and mutations, as well as aberrant epigenetic or transcriptional regulation and changes in tumour–stromal interactions in the tumour microenvironment, can lead to the development and/or progression of cancer. Similar to other kinase alterations, such alterations are targetable using small molecules or antibodies, and the benefits of FGFR inhibitors have been demonstrated in clinical trials involving subsets of patients with solid tumours harbouring FGFR alterations. However, the response rates in patients with FGFR alterations were relatively low, and responses in patients without detectable FGFR alterations were also observed. In this Review, the author describes the clinical experience with FGFR inhibitors to date, and highlights key aspects that might lead to improved response rates and/or the avoidance of acquired resistance, including the selection of patients who are most likely to benefit from treatment, and the use of FGFR inhibitors in combination regimens with other agents. FGFR alterations can be detected in a small subset of many different cancer types. Inspired by the successes with other targeted therapies, preliminary attempts to target FGFR-altered cancers have been hampered by low response rates and acquired resistance. In this Review, the author describes the development of FGFR inhibitors thus far, and provides guidance on future research priorities. Key points FGFR1 -amplified oestrogen receptor-positive breast cancer and lung squamous cell carcinoma, FGFR2 -amplified gastric cancer, FGFR2 -fusion-positive intrahepatic cholangiocarcinoma, FGFR2 -mutant endometrial uterine cancer and FGFR3 -mutant urothelial carcinoma can all be treated using FGFR inhibitors. Small-molecule inhibitors are the main therapeutic modality used to target FGFR signalling; these agents are classified as either FGFR1/2/3 inhibitors, FGFR4 inhibitors, pan-FGFR inhibitors and multikinase FGFR inhibitors. Antibody-based agents, FGF traps and RNA/DNA aptamers are also under investigation as FGFR-targeted therapeutics. Clinical trials have demonstrated the benefits of FGFR inhibitors in subsets of patients, but also low response rates and the emergence of acquired resistance owing to activation of bypass signalling, gatekeeper mutations and intratumour heterogeneity