Herceptin - Mechanism of Action

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(Figure 1) Structure of the extracellular region of HER2 complexed with Herceptin Fab(1n8z)
(Figure 1) Structure of the extracellular region of HER2 complexed with Herceptin Fab(1n8z)

Basics

Introduction

Breast cancer is the most common type of cancer found among women except for skin cancers[1]. Although it is rarely seen in men, one in eight women will be diagnosed with breast cancer within their lifetime. Patients exhibiting an over-expression of Human Epidermal Growth Factor Receptor 2 (HER2) account for 25% of all breast cancer [2][3]. HER2+ patients often experience a more aggressive cancer resulting in more metastasized tumors [3]. The statistics show a poor prognosis for HER2+ patients with a 5-year survival rate of 68%. Herceptin (also known as trastuzumab) was approved by the FDA in September of 1998 for HER2+ patients and has been shown to be an effective tool in the battle against breast cancer [4].

HER2

HER2 is one of four human epidermal growth factor receptors (EGFR , HER2, HER3, and HER4)[5][6]. These receptors are part of a family of receptor tyrosine kinases responsible for cell proliferation and differentiation[2][7].
(Figure 2) HER family
(Figure 2) HER family[3]
This family is known as the ErbB family, because they are encoded by the ERBB genes, and is also known as the HER family. The HER family (refer to figure 2 and figure 5) are plasma membrane-bound receptors that contain an extracellular ligand-binding domain, a transmembrane domain, and an intracellular domain [3].

These human epidermal growth factor receptors exist on the cell surface and, with the exception of HER2, bind to specific ligands (epidermal growth factors) [2]. Over 11 different ligands for the epidermal growth factor receptors have been identified [5]. After the ligand binds to the receptor the receptor is able to homodimerize or heterodimerize with one another [8]. Dimerization is a chemical interaction between two "like" molecules in which they form a union. This dimerization causes a cross-phosphorylation of the intracellular tyrosine kinases between the two receptors and ultimately activates a cell signaling pathway.

HER2 is the only receptor within this family that is constitutively active being able to dimerize with other HER family members acting in a ligand-independent manner [2][8]. This continuous activation of the cell signal pathway causes an increase in cell division; thus, potentially causing a tumor. [8]

(Figure 3) Herceptin
(Figure 3) Herceptin [9]

Herceptin

Herceptin, generic trastuzumab, is a monoclonal antibody (refer to figure 3)[10]. Herceptin is an effective treatment for breast cancer for the reason that it binds to the extracellular domain of HER2 and by multiple mechanisms of action can prevent cell proliferation as well as target these HER2+ cells for destruction by the immune system [3][10].

Crystal structure of extracellular domain of human HER2 complexed with Herceptin Fab (PDB entry 1n8z)

(Figure 6) This picture illustrates the mechanism in which EGFR, HER3, and HER4 change conformation in order to dimerize and activate further cell signaling. A) Sub-domain I (green) is sepearated from sub-domain III (blue). Sub-domain II (red) forms an interaction (purple line) with sub-domain IV (yellow). This conformation allows sub-domain II to be hidden and unavailable for dimerization. B) The interaction between sub-domain II and sub-domain IV can be temporarily broken allowing for the receptor to become more available for ligand-binding. C) Upon ligand-binding, if the interaction of sub-domain II and IV is still formed, the interaction between sub-domain II and sub-domain IV is broken and allows sub-domain II to become available for homo- or hetero-dimerization with another receptor from the HER family.
(Figure 6) This picture illustrates the mechanism in which EGFR, HER3, and HER4 change conformation in order to dimerize and activate further cell signaling. A) Sub-domain I (green) is sepearated from sub-domain III (blue). Sub-domain II (red) forms an interaction (purple line) with sub-domain IV (yellow). This conformation allows sub-domain II to be hidden and unavailable for dimerization. B) The interaction between sub-domain II and sub-domain IV can be temporarily broken allowing for the receptor to become more available for ligand-binding. C) Upon ligand-binding, if the interaction of sub-domain II and IV is still formed, the interaction between sub-domain II and sub-domain IV is broken and allows sub-domain II to become available for homo- or hetero-dimerization with another receptor from the HER family[12].

References

  1. "What Are the Key Statistics about Breast Cancer?" Breast Cancer. Cancer.org, 31 Oct. 2012. Web. Nov. 2012. <http://www.cancer.org/cancer/breastcancer/detailedguide/breast-cancer-key-statistics>.
  2. 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 Cho, Hyun-Soo, Karen Mason, Kasra X. Ramyar, Ann Marie Stanley, Sandra B. Gabelli, Dan W. Denney, Jr., and Daniel J. Leahy. "Structure of the Extracellular Region of HER2 Alone and in Complex with the Herceptin Fab." Letters to Nature 421 (2003): 756-60. PubMed.gov. Web. Oct. 2012.
  3. 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 3.15 "HER2 Dimerization: A Key Component of Oncogenic Signaling in HER2 Breast Cancer." HER2+ Breast Cancer. Genentech, n.d. Web. 09 Nov. 2012. <http://www.biooncology.com/research-education/hdis/her2-dimerization/index.html>.
  4. "Herceptin Development Timeline." Genentech: Medicines. Genentech, n.d. Web. Nov. 2012. <http://www.gene.com/gene/products/information/oncology/herceptin/timeline.html>.
  5. 5.0 5.1 Bazley, L. A., and W. J. Gullick. "The Epidermal Growth Factor Receptor Family." Endocrine-Related Cancer. Society for Endocrinology and European Society of Endocrinology, 2005. Web. Oct. 2012. <http://erc.endocrinology-journals.org/content/12/Supplement_1/S17.full>.
  6. 6.0 6.1 Satyanarayanajois, Seetharama, Stephanie Villalba, Liu Jianchao, and Go Mei Lin. "Design, Synthesis, and Docking Studies of Peptidomimetics." Chem. Biol. Drug Des. 74.3 (2009): 246-57. National Institute of Health. Web. Nov. 2012. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2866155/pdf/nihms-190276.pdf>.
  7. Banappagari, Sashikanth, Sharon Ronald, and Seetharama Satyanarayanajois. "Structure-activity Relationship of Conformationally Constrained." Medchemcomm. 2.8 (2011): 752-59. National Institute of Health. Web. Oct. 2012. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3163471/pdf/nihms308284.pdf>.
  8. 8.0 8.1 8.2 8.3 "HER Pathways Are of Critical Importance in Cancer." HER Receptors Overview. Genentech, n.d. Web. 09 Nov. 2012. <http://www.biooncology.com/research-education/her/overview/index.html>.
  9. Ryzhkov, Andrew. "Trastuzumab." Wikipedia. Wikimedia Foundation, 11 Aug. 2012. Web. 09 Nov. 2012. <http://en.wikipedia.org/wiki/Trastuzumab>.
  10. 10.0 10.1 Jiang, Beihai, Wenbin Liu, Hong Qu, Lin Meng, Shumei Song, Tao Ouyang, and Chengchao Shou. "A Novel Peptide Isolated from a Phage Display Peptide Library with." The Journal of Biological Chemistry 280.6 (2005): 4656-662. The Journal of Biological Chemistry. Web. Oct. 2012. <http://www.jbc.org/content/280/6/4656.full.pdf+html>.
  11. 11.0 11.1 "ERBB2." Genetics Home Reference. U.S. National Library of Medicine, 5 Nov. 2012. Web. 09 Nov. 2012. <http://ghr.nlm.nih.gov/gene/ERBB2>.
  12. 12.0 12.1 12.2 Lammerts Van Bueren, Jeroen, Wim K. Bleeker, Annika Bra¨ Nnstro¨m, Anne Von Euler, Magnus Jansson, Matthias Peipp, Tanja Schneider-Merck, Thomas Valerius, Jan G. J. Van De Winkel, and Paul W. Parren. "The Antibody Zalutumumab Inhibits Epidermal Growth." PNAS 105.16 (2008): 6109-114. Web. Nov. 2012. <http://www.pnas.org/content/105/16/6109/F1.expansion.html>.
  13. Saxon, Marian L., and David C. Lee. "Mutagenesis Reveals a Role for Epidermal Growth Factor Receptor Extracellular Subdomain IV in Ligand Binding." The Journal of Biological Chemistry 274.40 (1999): 28356-8362. PubMed.gov. Web. Oct. 2012. <http://www.jbc.org/content/274/40/28356.long>.
  14. 14.0 14.1 14.2 14.3 14.4 14.5 Gajria, Devika, and Sarat Chandarlapaty. HER2-amplified Breast Cancer: Mechanisms of Trastuzumab 11.2 (2011): 263-75. National Institute of Health. Web. Oct. 2012. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3092522/pdf/nihms289124.pdf>.

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