SMPDB

Pathway Description

Bevacizumab Action Pathway

Homo sapiens

Drug Action Pathway

Created: 2013-08-22

Last Updated: 2025-01-29

Bevacizumab is a humanized anti-VEGF monoclonal antibody used in the treatment of cancer. Cancer cells tend to overexpress VEGF, which stimulates angiogenesis, facilitating cancer growth and metastasis. The majority of VEGF’s effects are mediated through its binding to the VEGFR-2 receptor on endothelial cell surfaces. Upon binding, the receptor autophosphorylates and initiates a signalling cascade, starting with the activation of CSK. CSK phosphorylates Raf-1, which subsequently phosphorylates MAP kinase kinase, which phosphorylates MAP kinase. The activated MAP kinase enters the nucleus and stimulates the expression of angiogenic factors resulting in increased cell proliferation, migration, permeability, invasion, and survival. Binding of VEGF to VEGFR-2 also activates phospholipase C PIP2 into DAG and IP3. DAG may be involved in the activation of Raf-1 leading to angiogenesis, while IP3 activates PI3K and triggers calcium release from the endoplasmic reticulum. This ultimately leads to the activation of nitric oxide synthase and the production of nitric oxide, which stimulates vasodilation and increases vascular permeability. In cancer, VEGF has also been shown to bind to the VEGFR-1 receptor. However, its effects on angiogenesis are unclear at the moment. There are some evidence to show that VEGFR-1 may cross-talk with VEGFR-2 and initiate the signalling cascades described above. Bevacizumab exerts its effect by binding to extracellular VEGF and preventing its binding to receptors on the endothelial cell surfaces. This in turns inhibits the MAP and IP3 and supresses angiogenesis.

References

Bevacizumab Pathway References

Hicklin DJ, Ellis LM: Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 2005 Feb 10;23(5):1011-27. doi: 10.1200/JCO.2005.06.081. Epub 2004 Dec 7.

Pubmed: 15585754

Ranieri G, Patruno R, Ruggieri E, Montemurro S, Valerio P, Ribatti D: Vascular endothelial growth factor (VEGF) as a target of bevacizumab in cancer: from the biology to the clinic. Curr Med Chem. 2006;13(16):1845-57.

Pubmed: 16842197

Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N: Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989 Dec 8;246(4935):1306-9. doi: 10.1126/science.2479986.

Pubmed: 2479986

Keck PJ, Hauser SD, Krivi G, Sanzo K, Warren T, Feder J, Connolly DT: Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science. 1989 Dec 8;246(4935):1309-12. doi: 10.1126/science.2479987.

Pubmed: 2479987

Tischer E, Mitchell R, Hartman T, Silva M, Gospodarowicz D, Fiddes JC, Abraham JA: The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J Biol Chem. 1991 Jun 25;266(18):11947-54.

Pubmed: 1711045

Terman BI, Dougher-Vermazen M, Carrion ME, Dimitrov D, Armellino DC, Gospodarowicz D, Bohlen P: Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochem Biophys Res Commun. 1992 Sep 30;187(3):1579-86. doi: 10.1016/0006-291x(92)90483-2.

Pubmed: 1417831

Waltenberger J, Claesson-Welsh L, Siegbahn A, Shibuya M, Heldin CH: Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. J Biol Chem. 1994 Oct 28;269(43):26988-95.

Pubmed: 7929439

Takahashi T, Shibuya M: The 230 kDa mature form of KDR/Flk-1 (VEGF receptor-2) activates the PLC-gamma pathway and partially induces mitotic signals in NIH3T3 fibroblasts. Oncogene. 1997 May 1;14(17):2079-89. doi: 10.1038/sj.onc.1201047.

Pubmed: 9160888

Shibuya M, Yamaguchi S, Yamane A, Ikeda T, Tojo A, Matsushime H, Sato M: Nucleotide sequence and expression of a novel human receptor-type tyrosine kinase gene (flt) closely related to the fms family. Oncogene. 1990 Apr;5(4):519-24.

Pubmed: 2158038

Kendall RL, Thomas KA: Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10705-9. doi: 10.1073/pnas.90.22.10705.

Pubmed: 8248162

Herley MT, Yu Y, Whitney RG, Sato JD: Characterization of the VEGF binding site on the Flt-1 receptor. Biochem Biophys Res Commun. 1999 Sep 7;262(3):731-8. doi: 10.1006/bbrc.1999.1282.

Pubmed: 10471394

Highlighted elements will appear in red.

Highlight Compounds

No Compounds Present

Highlight Proteins

	Bevacizumab
	Vascular endothelial growth factor A
	Vascular endothelial growth factor receptor 1
	Vascular endothelial growth factor receptor 2

Enter relative concentration values (without units). Elements will be highlighted in a color gradient where red = lowest concentration and green = highest concentration. For the best results, view the pathway in Black and White.

Visualize Compound Data

No Compounds Present

Visualize Protein Data