INTRODUCTION: Metastatic clear-cell renal cell carcinoma (RCC) is a highly 
vascularized tumor type that is often associated with inactivating mutations in 
the von Hippel-Lindau gene that ultimately drives pro-angiogenic signaling 
pathways, including the VEGF pathway. As such, new therapies indicated for RCC 
have largely focused on blocking angiogenesis by inhibiting this pathway. 
Despite the contribution of these agents to clinical outcomes in RCC, acquired 
resistance that stimulates tumor regrowth and revascularization quickly emerges. 
Resistance to VEGF inhibition appears to largely result from activation of 
compensatory angiogenesis pathways (including the fibroblast growth factor [FGF] 
pathway), providing a rationale to investigate their inhibition.
AREAS COVERED: This review explores the role of the FGF pathway in resistance to 
VEGF-targeted therapy and rationale for targeting in RCC. PubMed, as well as 
ASCO and ESMO congress abstracts, were searched for preclinical and clinical 
data for FGF inhibitors in RCC.
EXPERT OPINION: The FGF pathway presents a logical target in RCC and trials of 
the FGF receptor inhibitors regorafenib, dovitinib, nintedanib, lenvatinib and 
cediranib demonstrated clinical activity. Clinical development should focus on 
optimizing the use of this therapy by improving patient selection and evaluating 
combined therapy.