Our bodies are made of countless cells, each operating under the precise instructions contained within our genes. These genes are segments of DNA that dictate how our cells grow, function, and even repair themselves. Occasionally, changes occur in these genetic instructions, known as mutations, which can alter a gene’s normal role and impact bodily processes. While many mutations are harmless, some can disrupt cellular regulation, leading to various health conditions.
What is the PIK3CA Gene?
The PIK3CA gene contains instructions for making p110 alpha (p110α), a component of the enzyme phosphatidylinositol 3-kinase (PI3K). This p110α protein functions as the catalytic subunit of the PI3K enzyme, with another protein regulating its activity. PI3K is involved in a process called phosphorylation, where it adds a phosphate group to other signaling molecules.
This action triggers a series of chemical signals within cells, forming a complex communication network. PI3K signaling is involved in various cell activities, including cell growth, division (proliferation), movement, protein production, and cell survival.
How PIK3CA Mutations Occur
A PIK3CA mutation involves a change in the DNA sequence of this gene, altering its normal instructions. These mutations commonly lead to a “gain-of-function,” where the PI3K enzyme becomes abnormally active, similar to an accelerator pedal constantly pressed down, causing uncontrolled cellular activity.
The altered p110α subunit, produced due to the mutation, leads to unregulated chemical signaling within cells, promoting continuous growth and division. These mutations are most often somatic, meaning they are acquired during a person’s lifetime rather than being inherited from parents. They arise randomly in a single cell during development or later in life.
More than 80% of these somatic mutations occur in specific regions of the PIK3CA gene: exon 9 (helical domain) and exon 20 (kinase domain). These “hotspot” mutations, such as E542K, E545K, and H1047R, cause the PI3K enzyme to become overactive. This overactivity drives unregulated signaling pathways that promote cell proliferation and survival.
PIK3CA Mutations and Cancer Development
The “gain-of-function” caused by PIK3CA mutations directly contributes to uncontrolled cell growth and division, a defining feature of cancer. The abnormally active PI3K enzyme triggers continuous chemical signals that override normal cellular checks and balances, allowing cells to multiply excessively and form tumors.
PIK3CA mutations are common in various cancers, often acting as “driver mutations” that fuel tumor growth. They are among the most frequent genetic alterations in solid tumors, found in over 12 different types. For instance, PIK3CA mutations are present in approximately 30-40% of all breast cancers, particularly in estrogen receptor-positive breast cancer.
Other cancers with a notable prevalence of activating PIK3CA mutations include endometrial cancer (over 30%), bladder cancer (over 20%), colorectal carcinoma (over 17%), and head and neck squamous cell carcinoma (over 15%). These mutations can also affect a cancer cell’s ability to resist programmed cell death (apoptosis) and to metastasize. Understanding the presence of these mutations is important, as it can influence the clinical behavior of tumors and guide treatment approaches.
Detecting and Targeting PIK3CA Mutations
Detecting PIK3CA mutations guides personalized cancer treatment plans. These mutations can be identified through various methods, including analyzing tumor tissue from biopsies. Liquid biopsies, which involve blood tests, can also detect circulating tumor DNA that carries these mutations. Accurate and timely identification of PIK3CA mutations is particularly important for breast cancer patients, as it determines their eligibility for specific treatments.
Once identified, PIK3CA mutations can be targeted with specific therapies. Targeted therapy involves drugs designed to block the overactive pathways caused by these mutations. For example, alpelisib is an oral PI3K inhibitor that specifically targets the p110α subunit, which is encoded by the PIK3CA gene. This drug is approved for use in combination with fulvestrant to treat postmenopausal women and men with hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced or metastatic breast cancer that has progressed after endocrine therapy.
Clinical trials, such as SOLAR-1, have shown that alpelisib combined with fulvestrant significantly improved progression-free survival in patients with PIK3CA-mutated breast cancer, nearly doubling it compared to fulvestrant alone. While other PI3K inhibitors have been explored, alpelisib has demonstrated a more manageable side effect profile. Detecting these mutations and using targeted therapies like alpelisib allows for more precise and effective cancer management.