Targeting Tyrosine kinases in Renal Cell Carcinoma: "New Bullets against Old Guys"

Abstract

Clear cell renal cell carcinoma (ccRCC) is the seventh most frequently diagnosed tumor in adults in Europe and represents approximately 2.5% of cancer deaths. The molecular biology underlying renal cell carcinoma (RCC) development and progression has been a key milestone in the management of this type of tumor. The discovery of Von Hippel Lindau (VHL) gene alterations that arouse in 50% of ccRCC patients, leads the identification of an intracellular accumulation of HIF and, consequently an increase of VEGFR expression. This change in cell biology represents a new paradigm in the treatment of metastatic renal cancer by targeting angiogenesis. Currently, there are multiple therapeutic drugs available for advanced disease, including therapies against VEGFR with successful results in patients´ survival. Other tyrosine kinases' pathways, including PDGFR, Axl or MET have emerged as key signaling pathways involved in RCC biology. Indeed, promising new drugs targeting those tyrosine kinases have exhibited outstanding efficacy. In this review we aim to present an overview of the central role of these tyrosine kinases' activities in relevant biological processes for kidney cancer and their usefulness in RCC targeted therapy development. In the immunotherapy era, angiogenesis is still an "old guy" that the medical community is trying to fight using "new bullets".

Keywords: Axl; Fibroblast Growth factor Receptor (FGFR); Kidney cancer; Platelet Derived Growth Factor Receptor (PDGFR); Tyrosine kinase; Tyrosine-Protein Kinase Met (MET); Vascular endothelial growth factor receptor (VEGFR).

Figure 1

Intracellular signaling triggered by VEGF receptors. Specific transmembrane receptor tyrosine kinase for VEGF, i.e., VEGFR 1–3, recruit PLCγ, Src and FYN in order to signal mainly through DAG receptors (PKC), PKA, Rac1, MEK and Akt/mTOR. Transcription factors activated by these signaling, including NFAT or AP1, will finally regulate gene expression associated to VEGFR/VEGF binding. Increased levels of intracellular calcium also linked to this binding will contribute to PKC and NFAT activation, among others.

Figure 2

MET triggered intracellular signaling. Binding of HGF to MET transmembrane receptor tyrosine kinase recruit PLCγ, GRB2 and SOS, which activate DAG receptors (PKC), RAS/RAF/MEK, PI3K/RAC and Akt/mTOR. These kinases lead to activation of transcription factors including NFκB or AP1 for gene expression.