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HER2 (ERBB2) Mutations in Non-Small Cell Lung Cancer: Mechanism of Disease.
The HER Receptor Family and HER2 (ERBB2) Mutations in Non-Small Cell Lung Cancer.
HER2, or human epidermal growth factor receptor 2, is 1 of 4 receptor tyrosine kinases in the HER family. These receptors can be activated to transmit intracellular signals through homodimerization or heterodimerization, resulting in cell growth, differentiation, movement, and survival.
During activation, the tyrosine kinase domain of EGFR, HER2, and HER4 becomes phosphorylated, but this activity is impaired in HER3. And while EGFR, HER3, and HER4 can initiate intracellular signaling by binding to a ligand, HER2 cannot.
Although HER2 has no known ligand, it is the preferred binding partner of the other HER receptors, and it provides the strongest activation across all possible heterodimers.
Alterations of EGFR and HER2 play a critical role in the pathogenesis of several cancers.
In lung adenocarcinoma, three subsets of HER2 alterations—HER2 gene amplification, HER2 receptor overexpression, and HER2 genetic mutations—have been investigated with anti-HER2 agents in clinical trials but with disappointing results.
Activating HER2 mutations, often called ERBB2 mutations, account for 2-4% of all lung adenocarcinomas, but they also play a role in other forms of cancer, including bladder, stomach, and cervical cancer.
HER2 is a membrane receptor. When mutated, it may lead to the development of non-small cell lung cancer and other cancers.
The Effect of HER2 (ERBB2) Mutations on Intracellular Signaling.
In lung adenocarcinoma, HER2 gene mutations, also called ERBB2 mutations, change the shape of the HER2 receptor and trigger hyperactive signaling.
Mutations rarely occur in the extracellular and transmembrane domains of HER2. But 80 to 90 percent of HER2 mutations in non-small cell lung cancer are in the kinase domain and are intrinsically resistant to many currently approved targeted therapies due to changes in the shape of the receptor.
Normally, HER2 signals through the PI3K and MAPK pathways, which stimulate cell growth, differentiation, movement, and survival. However, mutations in HER2 make the receptor hyperactive and increase its rate of heterodimerization, even in the absence of a true ligand. This promotes uncontrolled cell growth and tumorigenesis. Mutations in HER2 can also affect the rate of receptor internalization.
HER2 gene mutations in non-small cell lung cancer may trigger hyperactive signaling that promotes uncontrolled cell growth and tumorigenesis.
The Effect of HER2 (ERBB2) Mutations on Receptor Internalization.
Receptor internalization is a process that transports large molecules such as proteins and transmembrane receptors into a cell. It is controlled by the action of receptors binding to their ligands. During internalization, the plasma membrane encloses a portion of the external environment to form an endosome.
Once inside an endosome, receptors and their ligands may either be recycled and return to the cell surface or be degraded inside a lysosome, allowing the release of nutrients back into the cell.
Therapeutic agents such as antibody-drug conjugates, which are investigational in non-small cell lung cancer, may rely on this natural mechanism of receptor internalization to release their cytotoxic payload inside the cell.
Like other receptors, HER2 receptors are internalized. However, the rate of HER2 internalization is faster when certain mutations exist in the extracellular or kinase domains.
HER2 mutations found in non-small cell lung cancer may increase the rate of HER2 receptor internalization. Antibody-drug conjugates, which are investigational in non-small cell lung cancer, may rely upon receptor internalization.
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