52IN - Signaling Pathways, Mechanisms of Resistance and Treatment Decisions in Renal Cell Cancer

Abstract

ABSTRACT Renal cell cancer (RCC) is a highly vascularised disease and angiogenesis plays a critical role in tumor growth and spreading. For this reason, the main angiogenic pathways, involving the Vascular endothelial growth factors (VEGFs), the VEGF receptors (VEGF-Rs), and the mammalian target of rapamycin (mTOR) are the targets of drugs that have dramatically improved the outcome of patients affected by this disease. An increasing number of active agents directed against the above targets and other angiogenesis-related proteins, including the Fibroblast growth factors (FGFs) and their receptors (FGF-Rs), is now available. However, a biologically-based therapeutic algorithm is still missing and the onset of drug resistance and the lack of validated biomarkers predictive of response to single agents and, more in general, to antiangiogenic drugs, do not allow to take full advantage of the therapeutic options available. Interlukin 8 (IL-8) and FGF seem to play a role in the induction of resistance to TKIs. IL-8 overexpression is associated to resistance to sunitinib and IL-8 gene polymorphisms correlate with survival in patients treated with pazopanib. Increases in the FGF/FGF-Rs signalling is observed as escape to inhibition of the VEGF-Rs by TKIs. On the other hand, activation of the PI3K/Akt pathway is responsible for the onset of resistance to mTOR inhibitors. Several studies are now extensively analyzing the predictive value of a variety of angiogenesis-related biomarkers, including soluble VEGF and VEGF-Rs, IL-8 expression and secretion, polymorphisms of VEGF and IL-8 genes, and VHL mutations. In addition imaging techniques are also under evaluation as promising dynamic biomarkers of antiangiogenic drugs activity or resistance in RCC. A better understanding of the mechanisms of resistance and the validation of reliable biomarkers predictive of drug activity or resistance will help to select patients who can benefit from current and future treatments. Disclosure The author has declared no conflicts of interest.