PIK3CA is a human gene that regulates various cellular functions including proliferation and invasion. Because it is an oncogene, its activation by either gene amplification or mutation results in a cellular growth advantage contributing toward cancer formation and progression.
The PI3-Kinase pathway is one of many signaling pathways that are important for cell growth, transformation, adhesion, apoptosis, survival, and invasion. PI3-kinases themselves are heterodimeric lipid kinases composed of catalytic and adaptor/regulatory subunits encoded by separate genes and alternative splicing. The PI3-Kinase enzyme family is organized under three main classes (class I, II, and III), and various subgroups have been categorized based on their primary structure, substrate specificity, and regulation.
The human PIK3CA gene is located on chromosome 3q26.32 and is ∼34 kb consisting of 20 coding exons. The protein contains 1,068 amino acids yielding a 124 kDa size protein. The PIK3CA protein contains five known functional domains including a p85 binding domain, a Ras binding domain, a protein kinase C homology 2 domain, a helical domain, and a kinase domain.
In general, two main genetic alterations can lead to oncogene activation in human malignancies. The first mechanism is gene amplification, in which a wild type gene is duplicated, usually involving multiple duplications, leading to increased protein production of the amplified gene. This increase in oncogenic protein continually activates downstream signaling molecules and pathways, thus driving cellular growth and transformation. For PIK3CA, gene amplification has been described in human cancers and precancerous lesions including breast cancers, ovarian cancers and thyroid adenomas. However, PIK3CA gene amplification appears to be a relatively uncommon event in most human malignancies. Rather, a second mechanism, somatic missense mutation, is the predominant method of PIK3CA gene activation found in most human cancers. Accordingly, the majority of PIK3CA mutations found in human malignancies occur in one of two domains, the helical and kinase domains. These mutations are predicted to render the kinase function of the protein as being constantly activated and experimental data has supported this supposition. PIK3CA mutations occur at a relatively high frequency in breast and colorectal cancers and at lower frequency in other solid malignancies. Strikingly, in most studies of activating PIK3CA missense mutations, three common “hotspot” mutations have been described, E542K, E545K, H1047R, with the first two mutations occurring in exon 9 (helical domain) and the third mutation affecting exon 20 (kinase domain). These frequently occurring mutations account for 80–90% of all PIK3CA mutations, and lend themselves as potential targets for diagnostic and therapeutic exploitation.
Frequently recurring “hotspot” mutations have many implications for clinical oncology. First and foremost, because these mutations are somatic, meaning they are present in the cancer cell but not in normal tissues, these PIK3CA mutations become obvious targets for therapeutic intervention since the “holy grail” of all cancer therapy relies upon isolating medicines capable of specifically killing cancer cells while leaving non-cancerous cells relatively unharmed. The somatic activating nature of these mutations therefore makes them perfect for this type of targeted therapy and indeed small molecule PIK3CA inhibitors are beginning to enter early phase clinical trials. Additionally, because activating “hotspot” mutations are so common in a number of different human malignancies, targeting these mutations for therapy could have a tremendous impact on the morbidity and mortality of human cancers. Second, these mutations could also be potentially useful as a more sensitive and specific means of cancer detection and/or diagnosis. For example, given newer technologies that enable the detection of single mutant molecules in blood and stool, it is tempting to speculate that genetic testing could be developed to either detect cancer cells with mutant PIK3CA as an adjunct to an initial screening test, or to use mutant PIK3CA as a molecular marker to detect metastatic disease and/or recurrent disease after treatment. Along those lines, the detection of mutant PIK3CA in human cancer may also lend itself as a prognostic indicator of disease recurrence, and clinical studies in a number of cancers are currently addressing this important question. Ultimately, the discovery of the PIK3CA oncogene as one of the most mutated oncogenes in human cancers makes it one of the most important cancer causing genes to date, and places it at the forefront for targeted drug development and cancer diagnostics.