Fibroblast growth factor receptors as therapeutic targets in clear-cell renal cell carcinoma

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.