PIK3CA

PIK3CA

PIK3CA is a gene that encodes the p110α catalytic subunit of phosphatidylinositol 3-kinase (PI3K), which is involved in the PI3K/AKT/mTOR pathway. This pathway is crucial for regulating cell growth, proliferation, differentiation, motility, survival, and intracellular trafficking, which are important for cancer development.

Structure

The PIK3CA gene is located on chromosome 3q26.3 and consists of 20 exons. The protein product, p110α, is a 1068 amino acid protein that forms a heterodimer with a regulatory subunit, typically p85, to form the active PI3K enzyme.

Function

PIK3CA plays a critical role in the PI3K/AKT/mTOR signaling pathway. Upon activation by receptor tyrosine kinases, PI3K phosphorylates the 3' hydroxyl group of the inositol ring of phosphatidylinositol (4,5)-bisphosphate (PIP2) to generate phosphatidylinositol (3,4,5)-trisphosphate (PIP3). PIP3 serves as a second messenger, recruiting proteins with pleckstrin homology domains, such as AKT, to the plasma membrane, where they are activated.

Clinical Significance

Mutations in PIK3CA are among the most common genetic alterations in human cancers, including breast cancer, colorectal cancer, and endometrial cancer. These mutations often lead to constitutive activation of the PI3K pathway, promoting oncogenic transformation and tumor progression.

Cancer

PIK3CA mutations are frequently observed in various cancers. The most common mutations occur in the helical (E542K, E545K) and kinase (H1047R) domains of the protein. These mutations result in increased kinase activity and downstream signaling, contributing to oncogenesis.

Therapeutic Target

Due to its role in cancer, PIK3CA is a target for cancer therapy. PI3K inhibitors, such as alpelisib, have been developed and approved for the treatment of PIK3CA-mutant cancers. These inhibitors aim to block the aberrant signaling caused by PIK3CA mutations.

Research

Ongoing research is focused on understanding the full spectrum of PIK3CA mutations and their impact on cancer biology. Studies are also exploring combination therapies that target multiple nodes in the PI3K/AKT/mTOR pathway to overcome resistance to PI3K inhibitors.

Also see

• Phosphatidylinositol 3-kinase
• AKT
• mTOR
• Breast cancer
• Colorectal cancer
• Endometrial cancer