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Inhibition of HER2

In This Section:

Inhibition of HER2

The epidermal growth factor receptor family consists of four cell surface receptors: EGF receptor, also called HER1; HER2/neu; HER3; and HER4. Binding of specific growth factors, or ligands, to three of these receptors causes them to interact, or dimerize, either with a receptor of the same type or with another family member. HER2 is called an "orphan receptor" because it does not interact directly with any ligand. Instead, it dimerizes with ligand-bound EGF receptor, HER3, or HER4.

A cross-section of a cell is shown, including the cell membrane, cytoplasm, and nucleus. There are several proteins of different colors spanning the membrane. Some of the proteins are labeled EGFR/HER1, HER2, HER3, and HER4.

A cross-section of a cell is shown in the background. A call-out circle in the foreground shows a magnified view of two proteins--EGFR and HER2--embedded in the membrane. EGFR is interacting with a growth factor and has dimerized with HER2.

Receptor dimerization activates signaling pathways inside the cell. These pathways lead to cell growth, proliferation, and survival.

A cross-section of a normal cell is shown in the background. EGFR has dimerized with HER and two HER2 receptors have dimerized. Active signaling pathways are coming from both pairs of dimerized receptors.

HER2 in Cancer Cells

The HER2 gene is amplified in 20% of breast cancers. This means that the cells of these cancers have extra copies of the HER2 gene. Breast cancers with amplified HER2 genes, referred to as HER2-positive cancers, make more HER2 protein than HER2-negative cancers.

This is a split-screen image. On the right is a normal cell in the background with a close-up view of chromosome 17 in an inset circle in the foreground. There is a single yellow band on the chromosome labeled, 'HER2 gene.' On the left is a cancer cell that overexpresses HER2 in the background. An inset circle in the foreground shows chromosome 17 with six yellow bands labeled, 'HER2 genes,' indicating that the HER2 gene has been amplified in the cancer cell.

The extra HER2 protein causes increased signal pathway activation, which contributes to the uncontrolled growth and survival of these cancers.

A cross-section of a cancer cell with many membrane-spanning receptors is shown. Three pairs of receptors represent activated, dimerized receptors. These dimers have activated intracellular signaling pathways, represented by a string of glowing yellow oval shapes.

Breast tumors that overexpress HER2 protein are more aggressive than other breast tumors. Patients with these tumors have a poorer prognosis and decreased chance of survival compared with patients whose tumors do not overexpress HER2.

Inhibiting HER2

Researchers have developed multiple strategies for interfering with HER2 signaling. These include a small molecule called lapatinib as well as monoclonal antibodies.

The screen is titled, 'Interfering with HER2 Signaling.' A silhouette of a woman is shown on the left side of the screen. Two icons are shown on the right side of the screen. The first icon, labeled 'Small Molecules,' shows three small purple ovoid shapes. The second icon, labeled 'Monoclonal Antibodies,' shows a single purple Y-shape.

Herceptin® (trastuzumab) is a monoclonal antibody that binds to HER2. This prevents the receptor from activating the pathways that promote the proliferation and survival of breast cancer cells.

This image shows a layer of pink normal with an embedded mass of green cancer cells. An inset circle in the foreground shows a close-up view of a cancer cell with multiple receptors spanning the cell membrane. A purple antibody is bound to one of the receptors and is preventing the receptor from interacting with another membrane-spanning receptor. An intracellular signaling pathway is colored gray to indicate that it is inactive.

Herceptin® (trastuzumab) may also interfere with cancer cell growth by activating an immune response.

This image shows a layer of pink normal with an embedded mass of green cancer cells. There are purple antibodies bound to the surface of some of the cancer cells. These antibodies have attracted blue immune cells that are releasing molecules that will damage nearby cells.

Herceptin® (trastuzumab) is used to treat breast cancer only if the tumor overexpresses HER2. It has been approved by the FDA for the treatment of metastatic breast cancer in combination with or following administration of standard chemotherapy. Herceptin® (trastuzumab) has also been approved by the FDA as an adjuvant treatment for some earlier-stage breast cancers. Adjuvant therapy is treatment given after primary therapy--for example, surgery--to increase the chances of long-term survival.

More Information

Herceptin

Herceptin® (trastuzumab) is approved by the FDA for the adjuvant treatment of HER2-overexpressing breast cancer that is either (1) axillary lymph node-positive or (2) axillary lymph node-negative with at least one high-risk feature (e.g., estrogen receptor/progesterone receptor-negative, pathologic tumor size greater than 2 cm, Grade 2-3, age less than 35 years):

Herceptin® (trastuzumab) is also approved by the FDA for use:

  • In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer.
  • As a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease.

More Information

Drugs that target EGFR family members (HER1 and HER2)

 Generic NameTrade NameDrug Type
EGFR (HER1) inhibitorsCetuximabErbitux®Monoclonal antibody
 LapatinibTykerb®*Small molecule
 GefitinibIressa®Small molecule
 ErlotinibTarceva®Small molecule
HER2 inhibitorsTrastuzumabHerceptin®*Monoclonal antibody
 PertuzumabOmnitarg™Monoclonal antibody
 LapatinibTykerb®*Small molecule

* Agents that have been approved by the FDA for treatment of breast cancer and/or reduction of risk of breast cancer

The small molecule inhibitors--Tykerb® (lapatinib), Iressa® (gefitinib), and Tarceva® (erlotinib)--interfere with the kinase activity of their target proteins. The monoclonal antibodies--Erbitux® (cetuximab), Herceptin® (trastuzumab), and Omnitarg™(pertuzumab)--interact with the extracellular portion of their target receptor proteins and prevent receptor interaction with growth factor and/or dimerization with other receptors.

For more information on types of targeted therapies, see Understanding Targeted Therapies: An Overview at http://www.cancer.gov/cancertopics/understandingcancer/targetedtherapies.

Self Test

Questions

  1. Possible mechanisms of action of Herceptin® (trastuzumab) include:
    1. Activation of an immune response.
    2. Reduction of circulating levels of growth factor.
    3. Both A and B.

Answers

  1. Correct Answer: a
    1. Correct.
      Herceptin® (trastuzumab) is thought to activate an immune response called antibody-dependent cell-mediated cytotoxicity. Other possible mechanisms of action include preventing the dimerization of EGFR family receptors, increasing the rate of degradation of HER2, and preventing the extracellular domain of HER2 from being processed properly.
    2. Incorrect.
      Herceptin® (trastuzumab) interacts with HER2, which is a cell surface receptor, and does not influence levels of circulating growth factor. Potential mechanisms of action of trastuzumab include activating an immune response, preventing the dimerization of EGFR family receptors, increasing the rate of degradation of HER2, and preventing the extracellular domain of HER2 from being processed properly.
    3. Incorrect.
      Trastuzumab interacts with HER2, which is a cell surface receptor, and does not influence levels of circulating growth factor. Potential mechanisms of action of Herceptin® (trastuzumab) include activation of an immune response, preventing the dimerization of EGFR receptors, increasing the rate of degradation of HER2, and preventing the extracellular domain of HER2 from being processed properly.