Paul
04-06-2004, 06:10 AM
The entire ErbB cell receptor family consists of the following:
1. EGFR (epidermal growth factor receptor), sometimes referred to as ErbB1 or HER-1;
2. ErbB2, generally referred to HER-2/neu,
3. ErbB3, generally referred to as HER-3; and
4. ErbB4, generally referred to as HER-4.
The entire ErbB receptor family plays a normal role in cell growth and regulation. When one or more receptor family members are overexpressed, they intensify biochemical signals in the cell, with the result that the cell proliferates without normal regulation and takes on malignant potential. At this website, we focus upon overexpression of HER-2/neu. As noted above, EGFR (HER-1) can also overexpress.
ErbB receptors are composed of three components, or domains:
1. an extracellular domain (ECD) located on the cell surface, to which ligands/growth factors bind;
2. a transmembrane domain that passes through the cell wall; and
3. an intracellular domain (ICD), which includes a kinase. The kinase catalyses the addition of a chemical group, a phosphate, to the receptor. That action creates a space onto which another protein can dock, setting off the next of the biochemical events that cascade through the cell. The exact structure of the kinase varies from one ErbB receptor type to another.
The "ligands" of ErbB1/EGFR/HER-1, that is, the molecules in the body that naturally bind and activate it, include epidermal growth factor (EGF), transforming growth factor alpha, and amphiregulin. ErbB2, also known as Her 2/neu, is the second member of the ErbB receptor family. No natural ligands specific for ErbB2 are known; it is thought to be activated when it pairs up with other members of the ErbB family, a process called "heterodimerisation."
Why does any of this matter? It is estimated that 50% to 80% of breast cancer may overexpress one or more members of the ErbB receptor family. If you can figure out a way to nullify the overexpression of a cancer cell's defective ERbB receptor, you may be able to stop the aggressive proliferation of that cell.
Keep in mind that each ErbB receptor runs from the outer cell surface or ECD, through the cell wall, to the inner region of the cell or the ICD.
For example, beginning with the portion of the receptor located on the surface of the cell wall (i.e., the extracellular domain), Herceptin ™ blocks the extracellular domain of HER-2 in an attempt to stop HER-2 from overexpressing. Erbitux™(IMC-C225) blocks the extracellular domain of HER-1 (also known as EGFR or ERBb1) in an attempt to stop HER-1 from overexpressing.
Next, move to the portion of the receptor located within the cell (i.e., the intracellular domain, which includes a kinase and associated kinase activity as described above). GSK 572016 blocks the kinase and associated kinase activity of ErbB1/HER-1 and ErbB2/HER-2, and is referred to as a dual tyrosine kinase inhibitor. Iressa blocks the kinase and kinase acitivity of only ErbB1/HER-1 and is referred to as tyrosine kinase inhibitor.
Omnitarg ™(2C4) is a humanized antibody and the first in a new class of agents known as HER dimerization inhibitors (HDIs). HDIs block the ability of the HER2 receptor to partner with other HER receptor family members (HER1/EGFR, HER3, and HER4). In cancer cells, interfering with HER2's ability to partner with other HER family receptors blocks cell signaling may ultimately lead to cancer cell growth inhibition and death of the cancer cell. Because of their unique mode of action, HDIs have the potential to work in a wide variety of tumors, including those that do not overexpress HER2.
Hopefully, this isn't too technical. It may give you some idea as to where the science is heading. If you can determine that breast cancer is caused, in part, by overexpression of ErbB receptor family members, e.g., EGFR/HER-1, HER-2, HER-3 and/or HER-4, pharmaceutical drugs can be created to target specific overexpressions with respect to specific receptors in an attempt to stop abnormal cell growth and proliferation.
In any event, "EGFR" stands for "epidermal growth factor receptor" and refers to the HER-1 receptor. It can be tested for overexpression. Drugs such as Iressa, GSK 572016, and Omnitarg may help reduce or eliminate the overexpression of HER-1 and the associated abnormal cell proliferation that can accompany such overexpression.
1. EGFR (epidermal growth factor receptor), sometimes referred to as ErbB1 or HER-1;
2. ErbB2, generally referred to HER-2/neu,
3. ErbB3, generally referred to as HER-3; and
4. ErbB4, generally referred to as HER-4.
The entire ErbB receptor family plays a normal role in cell growth and regulation. When one or more receptor family members are overexpressed, they intensify biochemical signals in the cell, with the result that the cell proliferates without normal regulation and takes on malignant potential. At this website, we focus upon overexpression of HER-2/neu. As noted above, EGFR (HER-1) can also overexpress.
ErbB receptors are composed of three components, or domains:
1. an extracellular domain (ECD) located on the cell surface, to which ligands/growth factors bind;
2. a transmembrane domain that passes through the cell wall; and
3. an intracellular domain (ICD), which includes a kinase. The kinase catalyses the addition of a chemical group, a phosphate, to the receptor. That action creates a space onto which another protein can dock, setting off the next of the biochemical events that cascade through the cell. The exact structure of the kinase varies from one ErbB receptor type to another.
The "ligands" of ErbB1/EGFR/HER-1, that is, the molecules in the body that naturally bind and activate it, include epidermal growth factor (EGF), transforming growth factor alpha, and amphiregulin. ErbB2, also known as Her 2/neu, is the second member of the ErbB receptor family. No natural ligands specific for ErbB2 are known; it is thought to be activated when it pairs up with other members of the ErbB family, a process called "heterodimerisation."
Why does any of this matter? It is estimated that 50% to 80% of breast cancer may overexpress one or more members of the ErbB receptor family. If you can figure out a way to nullify the overexpression of a cancer cell's defective ERbB receptor, you may be able to stop the aggressive proliferation of that cell.
Keep in mind that each ErbB receptor runs from the outer cell surface or ECD, through the cell wall, to the inner region of the cell or the ICD.
For example, beginning with the portion of the receptor located on the surface of the cell wall (i.e., the extracellular domain), Herceptin ™ blocks the extracellular domain of HER-2 in an attempt to stop HER-2 from overexpressing. Erbitux™(IMC-C225) blocks the extracellular domain of HER-1 (also known as EGFR or ERBb1) in an attempt to stop HER-1 from overexpressing.
Next, move to the portion of the receptor located within the cell (i.e., the intracellular domain, which includes a kinase and associated kinase activity as described above). GSK 572016 blocks the kinase and associated kinase activity of ErbB1/HER-1 and ErbB2/HER-2, and is referred to as a dual tyrosine kinase inhibitor. Iressa blocks the kinase and kinase acitivity of only ErbB1/HER-1 and is referred to as tyrosine kinase inhibitor.
Omnitarg ™(2C4) is a humanized antibody and the first in a new class of agents known as HER dimerization inhibitors (HDIs). HDIs block the ability of the HER2 receptor to partner with other HER receptor family members (HER1/EGFR, HER3, and HER4). In cancer cells, interfering with HER2's ability to partner with other HER family receptors blocks cell signaling may ultimately lead to cancer cell growth inhibition and death of the cancer cell. Because of their unique mode of action, HDIs have the potential to work in a wide variety of tumors, including those that do not overexpress HER2.
Hopefully, this isn't too technical. It may give you some idea as to where the science is heading. If you can determine that breast cancer is caused, in part, by overexpression of ErbB receptor family members, e.g., EGFR/HER-1, HER-2, HER-3 and/or HER-4, pharmaceutical drugs can be created to target specific overexpressions with respect to specific receptors in an attempt to stop abnormal cell growth and proliferation.
In any event, "EGFR" stands for "epidermal growth factor receptor" and refers to the HER-1 receptor. It can be tested for overexpression. Drugs such as Iressa, GSK 572016, and Omnitarg may help reduce or eliminate the overexpression of HER-1 and the associated abnormal cell proliferation that can accompany such overexpression.