Elsevier

Pharmacological Research

Volume 120, June 2017, Pages 116-132
Pharmacological Research

Invited Review
Vascular endothelial growth factor (VEGF) and VEGF receptor inhibitors in the treatment of renal cell carcinomas

https://doi.org/10.1016/j.phrs.2017.03.010Get rights and content

Abstract

One Von Hippel-Lindau (VHL) tumor suppressor gene is lost in most renal cell carcinomas while the nondeleted allele exhibits hypermethylation-induced inactivation or inactivating somatic mutations. As a result of these genetic modifications, there is an increased production of VEGF-A and pro-angiogenic growth factors in this disorder. The important role of angiogenesis in the pathogenesis of renal cell carcinomas and other tumors has focused the attention of investigators on the biology of VEGFs and VEGFR1–3 and to the development of inhibitors of the intricate and multifaceted angiogenic pathways. VEGFR1–3 contain an extracellular segment with seven immunoglobulin-like domains, a transmembrane segment, a juxtamembrane segment, a protein kinase domain with an insert of about 70 amino acid residues, and a C-terminal tail. VEGF-A stimulates the activation of preformed VEGFR2 dimers by the auto-phosphorylation of activation segment tyrosines followed by the phosphorylation of additional protein-tyrosines that recruit phosphotyrosine binding proteins thereby leading to signalling by the ERK1/2, AKT, Src, and p38 MAP kinase pathways. VEGFR1 modulates the activity of VEGFR2, which is the chief pathway in vasculogenesis and angiogenesis. VEGFR3 and its ligands (VEGF-C and VEGF-D) are involved primarily in lymphangiogenesis. Small molecule VEGFR1/2/3 inhibitors including axitinib, cabozantinib, lenvatinib, sorafenib, sunitinib, and pazopanib are approved by the FDA for the treatment of renal cell carcinomas. Most of these agents are type II inhibitors of VEGFR2 and inhibit the so-called DFG-Aspout inactive enzyme conformation. These drugs are steady-state competitive inhibitors with respect to ATP and like ATP they form hydrogen bonds with the hinge residues that connect the small and large protein kinase lobes. Bevacizumab, a monoclonal antibody that binds to VEGF-A, is also approved for the treatment of renal cell carcinomas. Resistance to these agents invariably occurs within one year of treatment and clinical studies are underway to determine the optimal sequence of treatment with these anti-angiogenic agents. The nivolumab immune checkpoint inhibitor is also approved for the second-line treatment of renal cell carcinomas. Owing to the resistance of renal cell carcinomas to cytotoxic drugs and radiation therapy, the development of these agents has greatly improved the therapeutic options in the treatment of these malignancies.

Section snippets

Clinical course of renal cell carcinomas

Tumors of the kidney arise from cells in its outer portion, or cortex, and from its inner portion, or medulla. Siegel et al. estimated that about 64,000 new cases of kidney cancer will be diagnosed in the United States in 2017 (41,000 men and 23,000 women) and 24,000 people will die of the disease (14,000 men and 10,000 women) [1]. Deaths from cancer of the kidney account for about 2.3% of all cancer-related mortalities in the United States. Symptoms which prompt a person with renal cell

An overview of new blood vessel formation

The circulation is required for transporting oxygen, nutrients, hormones, and growth factors to and the removal of carbon dioxide and catabolites from cells and organs [6]. New blood vessel formation, or neovascularization, is divided into vasculogenesis and angiogenesis. The former is the process of new blood vessel formation from angioblasts that occurs during embryonic development. The latter is the process of new blood vessel formation from pre-existing vasculature. Signaling by the VEGF

Structure of VEGFR2-drug complexes

Axitinib is an inhibitor of VEGFR1/2/3 protein-tyrosine kinases that is approved as a second-line treatment for metastatic renal cell carcinomas (Table 5). The X-ray structure shows that the Nsingle bondH group of the axitinib indazole scaffold (Fig. 7A) forms a hydrogen bond with the hinge E917 carbonyl group of VEGFR2 while the N2 nitrogen of the scaffold forms a second hydrogen bond with the Nsingle bondH group of the F918 [68]. Because the enzyme has the DFG-Dout conformation, the αC-E885 carboxylate is able to

Epilogue

Maharaj et al. surveyed the expression of VEGF-A and VEGFR2 in the adult mouse [106]. They found that VEGF-A is expressed in all vascularized organs and tissues. It was expressed in close proximity to fenestrated blood vessels within endocrine glands, the choroid plexus, and kidney glomeruli. Fenestrae are the small pores in endothelial cells that allow for the transfer of small molecules and proteins with the surrounding tissue. In general VEGF-A is not expressed by endothelial cells, but

Acknowledgments

The colored figures in this paper were checked to ensure that their perception was accurately conveyed to colorblind readers [111]. The author thanks Laura M. Roskoski for providing editorial and bibliographic assistance.

References (111)

  • S. Iyer et al.

    Crystal structure of human vascular endothelial growth factor-B: identification of amino acids important for receptor binding

    J. Mol. Biol.

    (2006)
  • V.M. Leppänen et al.

    Structural determinants of vascular endothelial growth factor-D receptor binding and specificity

    Blood

    (2011)
  • S. Iyer et al.

    The crystal structure of human placenta growth factor-1 (PlGF-1), an angiogenic protein, at 2.0 A resolution

    J. Biol. Chem.

    (2001)
  • J. Lagercrantz et al.

    A comparative study of the expression patterns for vegf, vegf-b/vrf and vegf-c in the developing and adult mouse

    Biochim. Biophys. Acta

    (1998)
  • S. Ogawa et al.

    A novel type of vascular endothelial growth factor, VEGF-E (NZ-7 VEGF), preferentially utilizes KDR/Flk-1 receptor and carries a potent mitotic activity without heparin-binding domain

    J. Biol. Chem.

    (1998)
  • K. Suto et al.

    Crystal structures of novel vascular endothelial growth factors (VEGF) from snake venoms: insight into selective VEGF binding to kinase insert domain-containing receptor but not to fms-like tyrosine kinase-1

    J. Biol. Chem.

    (2005)
  • B.I. Terman et al.

    Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor

    Biochem. Biophys. Res. Commun.

    (1992)
  • C.J. Robinson et al.

    Evaluation of placenta growth factor and soluble Fms-like tyrosine kinase 1 receptor levels in mild and severe preeclampsia

    Am. J. Obstet. Gynecol.

    (2006)
  • M. Jeltsch et al.

    Vascular endothelial growth factor (VEGF)/VEGF-C mosaic molecules reveal specificity determinants and feature novel receptor binding patterns

    J. Biol. Chem.

    (2006)
  • M.A. Lemmon et al.

    Cell signaling by receptor tyrosine kinases

    Cell

    (2010)
  • R.L. Kendall et al.

    Vascular endothelial growth factor receptor KDR tyrosine kinase activity is increased by autophosphorylation of two activation loop tyrosine residues

    J. Biol. Chem.

    (1999)
  • L. Wei et al.

    Expression, characterization, and crystallization of the catalytic core of the human insulin receptor protein-tyrosine kinase domain

    J. Biol. Chem.

    (1995)
  • R.D. Meyer et al.

    A single amino acid substitution in the activation loop defines the decoy characteristic of VEGFR-1/FLT-1

    J. Biol. Chem.

    (2006)
  • A. Salameh et al.

    Direct recruitment of CRK and GRB2 to VEGFR-3 induces proliferation, migration, and survival of endothelial cells through the activation of ERK, AKT, and JNK pathways

    Blood

    (2005)
  • L.E. Locascio et al.

    KIDs rule: regulatory phosphorylation of RTKs

    Trends Biochem. Sci.

    (2013)
  • S.S. Taylor et al.

    Protein kinases: evolution of dynamic regulatory proteins

    Trends Biochem. Sci.

    (2011)
  • R. Roskoski

    A historical overview of protein kinases and their targeted small molecule inhibitors

    Pharmacol. Res.

    (2015)
  • R. Roskoski

    The ErbB/HER family of protein-tyrosine kinases and cancer

    Pharmacol. Res.

    (2014)
  • R. Roskoski

    Src protein-tyrosine kinase structure, mechanism, and small molecule inhibitors

    Pharmacol. Res.

    (2015)
  • R. Roskoski

    Classification of small molecule protein kinase inhibitors based upon the structures of their drug-enzyme complexes

    Pharmacol. Res.

    (2016)
  • R. Roskoski

    ERK1/2 MAP kinases: structure, function, and regulation

    Pharmacol. Res.

    (2012)
  • A. Álvarez-Aznar et al.

    VEGF receptor tyrosine kinases: key regulators of vascular function

    Curr. Top. Dev. Biol.

    (2017)
  • R. Roskoski

    Ibrutinib inhibition of Bruton protein-tyrosine kinase (BTK) in the treatment of B cell neoplasms

    Pharmacol. Res.

    (2016)
  • R. Roskoski

    Janus kinase (JAK) inhibitors in the treatment of inflammatory and neoplastic diseases

    Pharmacol. Res.

    (2016)
  • R. Roskoski

    Cyclin-dependent protein kinase inhibitors including palbociclib as anticancer drugs

    Pharmacol. Res.

    (2016)
  • R. Roskoski

    Allosteric MEK1/2 inhibitors including cobimetanib and trametinib in the treatment of cutaneous melanomas

    Pharmacol. Res.

    (2017)
  • R. Roskoski

    Sunitinib: a VEGF and PDGF receptor protein kinase and angiogenesis inhibitor

    Biochem. Biophys. Res. Commun.

    (2007)
  • R. Roskoski

    VEGF receptor protein-tyrosine kinases: structure and regulation

    Biochem. Biophys. Res. Commun.

    (2008)
  • Y.A. Muller et al.

    VEGF and the Fab fragment of a humanized neutralizing antibody: crystal structure of the complex at 2.4 A resolution and mutational analysis of the interface

    Structure

    (1998)
  • C. Wiesmann et al.

    Crystal structure at 1. 7 A resolution of VEGF in complex with domain 2 of the Flt-1 receptor

    Cell

    (1997)
  • B.I. Rini et al.

    Resistance to targeted therapy in renal-cell carcinoma

    Lancet Oncol.

    (2009)
  • R.L. Siegel et al.

    Cancer statistics, 2017

    CA Cancer J. Clin.

    (2017)
  • H.T. Cohen et al.

    Renal-cell carcinoma

    N. Engl. J. Med.

    (2005)
  • H.I. Scher et al.

    Bladder and renal cell carcinomas

  • E. Jonasch et al.

    Renal cell carcinoma

    BMJ

    (2014)
  • C.E. Alpers et al.

    The kidney

  • R. Roskoski

    The preclinical profile of crizotinib for the treatment of non-small-cell lung cancer and other neoplastic disorders

    Expert Opin. Drug Discov.

    (2013)
  • N. Ferrara

    Vascular endothelial growth factor: basic science and clinical progress

    Endocr. Rev.

    (2004)
  • J. Folkman

    Tumor angiogenesis: therapeutic implications

    N. Engl. J. Med.

    (1971)
  • M. Relf et al.

    Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor β-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis

    Cancer Res.

    (1997)
  • Cited by (198)

    View all citing articles on Scopus
    View full text