Mechanisms of action of sunitinib (VEGF-tyrosine kinase inhibitor) and mechanisms of drug resistance in renal cell carcinoma.

Sunitinib is a small molecule TKI, inhibiting activation of VEGF-R and PDGF-R, blocking intracellular pathways mediating cellular growth and angiogenesis. Mechanisms of resistance include upregulation of HIF pathways to stimulate angiogenesis and subsequent tumor growth. Lysosome sequestration of sunitinib contributes to reduced drug efficacy and resistance. Pro-angiogenic factors are inhibited by ICI-mediated anti-angiogenic therapy, which contributes to hypoxia. VEGF, Vascular endothelial growth factor; TKI, tyrosine kinase inhibitor; ICI, immune checkpoint inhibitor; HIF, hypoxia-inducible factor; PI3K, phosphoinositide 3-kinase; VEGF-R, vascular endothelial growth factor receptor; PDGF-R, platelet-derived growth factor receptor; mTOR, mammalian target of rapamycin; AKT, protein kinase B.