Activating mutations

1. Activating Mutations

An activating mutation is a type of genetic alteration that results in a gain of function of the gene product. These mutations often lead to increased activity of a protein, which can have significant implications in various biological processes and diseases, particularly in oncology.

Mechanism

Activating mutations typically occur in genes that encode proteins involved in signaling pathways. These mutations can lead to the constitutive activation of a protein, meaning the protein is active even in the absence of normal regulatory signals. This can result from changes in the protein's structure that mimic the active state or from alterations that prevent the protein from being turned off.

Common mechanisms by which activating mutations occur include:

• **Point mutations**: A single nucleotide change that results in an amino acid substitution, leading to a gain of function.
• **Insertions or deletions**: Small insertions or deletions that alter the protein structure, enhancing its activity.
• **Gene amplification**: An increase in the number of copies of a gene, leading to overexpression of the protein.

Examples in Disease

Activating mutations are frequently implicated in cancer. For example:

• **BRAF V600E mutation**: This is a well-known activating mutation in the BRAF gene, leading to continuous activation of the MAPK/ERK signaling pathway, which promotes cell proliferation and survival. It is commonly found in melanoma and other cancers.
• **EGFR mutations**: Certain mutations in the epidermal growth factor receptor (EGFR) gene result in constitutive activation of the receptor, driving the growth of non-small cell lung cancer.
• **KIT mutations**: Activating mutations in the KIT gene are associated with gastrointestinal stromal tumors (GISTs) and other malignancies.

Implications for Treatment

The identification of activating mutations has significant implications for the development of targeted therapies. Drugs that specifically inhibit the activity of the mutated protein can be highly effective. For instance:

• **BRAF inhibitors**: Such as vemurafenib, are used to treat cancers with BRAF V600E mutations.
• **EGFR inhibitors**: Like gefitinib and erlotinib, target EGFR mutations in lung cancer.
• **KIT inhibitors**: Imatinib is used to treat GISTs with KIT mutations.

Also see

• Oncogene
• Tumor suppressor gene
• Signal transduction
• Genetic mutation