PIK3CA

Official Full Name

phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha

Organism

Homo sapiens

GeneID

5290

Background

Phosphatidylinositol 3-kinase is composed of an 85 kDa regulatory subunit and a 110 kDa catalytic subunit. The protein encoded by this gene represents the catalytic subunit, which uses ATP to phosphorylate PtdIns, PtdIns4P and PtdIns(4,5)P2. This gene has been found to be oncogenic and has been implicated in cervical cancers. A pseudogene of this gene has been defined on chromosome 22. [provided by RefSeq, Apr 2016]

Synonyms

HMH; MCM; CCM4; CWS5; MCAP; PI3K; CLAPO; CLOVE; MCMTC; PI3K-alpha; p110-alpha;

Bio Chemical Class

Kinase

Protein Sequence

MPPRPSSGELWGIHLMPPRILVECLLPNGMIVTLECLREATLITIKHELFKEARKYPLHQLLQDESSYIFVSVTQEAEREEFFDETRRLCDLRLFQPFLKVIEPVGNREEKILNREIGFAIGMPVCEFDMVKDPEVQDFRRNILNVCKEAVDLRDLNSPHSRAMYVYPPNVESSPELPKHIYNKLDKGQIIVVIWVIVSPNNDKQKYTLKINHDCVPEQVIAEAIRKKTRSMLLSSEQLKLCVLEYQGKYILKVCGCDEYFLEKYPLSQYKYIRSCIMLGRMPNLMLMAKESLYSQLPMDCFTMPSYSRRISTATPYMNGETSTKSLWVINSALRIKILCATYVNVNIRDIDKIYVRTGIYHGGEPLCDNVNTQRVPCSNPRWNEWLNYDIYIPDLPRAARLCLSICSVKGRKGAKEEHCPLAWGNINLFDYTDTLVSGKMALNLWPVPHGLEDLLNPIGVTGSNPNKETPCLELEFDWFSSVVKFPDMSVIEEHANWSVSREAGFSYSHAGLSNRLARDNELRENDKEQLKAISTRDPLSEITEQEKDFLWSHRHYCVTIPEILPKLLLSVKWNSRDEVAQMYCLVKDWPPIKPEQAMELLDCNYPDPMVRGFAVRCLEKYLTDDKLSQYLIQLVQVLKYEQYLDNLLVRFLLKKALTNQRIGHFFFWHLKSEMHNKTVSQRFGLLLESYCRACGMYLKHLNRQVEAMEKLINLTDILKQEKKDETQKVQMKFLVEQMRRPDFMDALQGFLSPLNPAHQLGNLRLEECRIMSSAKRPLWLNWENPDIMSELLFQNNEIIFKNGDDLRQDMLTLQIIRIMENIWQNQGLDLRMLPYGCLSIGDCVGLIEVVRNSHTIMQIQCKGGLKGALQFNSHTLHQWLKDKNKGEIYDAAIDLFTRSCAGYCVATFILGIGDRHNSNIMVKDDGQLFHIDFGHFLDHKKKKFGYKRERVPFVLTQDFLIVISKGAQECTKTREFERFQEMCYKAYLAIRQHANLFINLFSMMLGSGMPELQSFDDIAYIRKTLALDKTEQEALEYFMKQMNDAHHGGWTTKMDWIFHTIKQHALN

Open

Disease

Breast cancer, Colorectal cancer, Follicular lymphoma, Malignant haematopoietic neoplasm, Prostate cancer, Rheumatoid arthritis, Solid tumour/cancer

Approved Drug

2 +

Clinical Trial Drug

9 +

Discontinued Drug

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Detailed Information

The catalytic subunit of phosphatidylinositol 3-kinase (PI3K), a fundamental enzyme in cellular signaling pathways controlling many cellular activities including growth, survival, and metabolism, is encoded by the PIK3CA gene. Found in 1994 by Volinia and associates using in situ hybridization methods, the gene is found at chromosome 3q26.32 and has 20 exons and an open reading frame of 3207 base pairs. Comprising 1068 amino acids and a molecular weight of over 124 kDa, the protein product is essential for oncogenesis and linked to many malignancies, including breast and cervical ones.

Structure and Function

Comprising a regulating component (85 kDa) and a catalytic subunit (110 kDa), the PI3K enzyme uses ATP, the protein encoded by PIK3CA reflects this catalytic component, which phosphatidylinositol 4-phosphate, phosphatidylinositol 4,5-bisphosphate, and phosphatidylinositol 4,5-bisphosphate. Essential second messengers, these phosphorylated products attract proteins with pleckstrin homology (PH) domains, like AKT1 and PDPK1, to the plasma membrane, thus activating signaling cascades linked in cell development, survival, and proliferation.

Oncogenic Potential and Mutations

Particularly observed for its recurring mutations in breast cancer, where PIK3CA is the most often mutated gene, PIK3CA has been widely described as an oncogene. Two primary hotspots for activating mutations arise in the helical domain at amino acids E542 and E545 and in the kinase domain at amino acid H1047. These mutations cause the PI3K/AKT signaling system to be aberrantly activated, a crucial actor in the spread of cancer. Furthermore, more than eighty percent of the found mutations focus on these areas, which greatly influences the activity of the enzyme and downstream signaling channels.

Apart from breast cancer, substantial mutation rates of PIK3CA have been reported in other malignancies including endometrial (over 30%), bladder (over 20%), colorectal (over 17%), and head and neck squamous cell cancers (over 15%). The Cancer Genome Atlas shows that second only to the tumor suppressor gene TP53, PIK3CA and PTEN are among the most often altered genes in over 12 solid tumor types.

Gene Expression and Regulation

PIK3CA is usually expressed in a non-activated form under physiological settings in many tissues, including the brain, lungs, breast, gastrointestinal system, cervix, and ovaries. It controls several fundamental physiological processes including survival, differentiation, and somatic cell proliferation. PIK3CA becomes highly active in the presence of activating mutations, which causes the protein to be overexpressed and consequent cellular transformation.

Comprising the class I PI3K family, the PIK3CA protein, or PI3Kp110α, is distinguished by its lipid kinase and protein kinase dual actions. Based on structural variations and activation processes, Class I PI3Ks are further classified as I-A and I-B. For example, Class I-A PI3Ks include a regulatory subunit (p85) and a catalytic subunit (p110). Two SH2 domains in the p85 subunit help to enable interactions with other signaling proteins including upstream receptor tyrosine kinases (RTKs). PI3Ks' activation as well as later signal transduction depends on this connection.

Figure 1 outlines the PI3K-AKT-mTOR signaling pathway, detailing how PI3K activation leads to the phosphorylation of key components that activate AKT, which in turn regulates mTOR to promote cellular growth, survival, and proliferation. Figure 1. PI3K-AKT-mTOR pathway. (Adimonye A, et al., 2018)

Implications in Cancer Therapy

Given its critical role in cancer, PIK3CA has been a significant focus of research and treatment development over the last two decades. Nowadays, PI3K inhibitors—which are either pan-PI3K inhibitors, PI3K subtype-selective inhibitors, or dual inhibitors aimed at both PI3K and mTOR pathways—have become very common. Because of their effects on many PI3K isoforms, which are engaged in essential physiological functions like immune response and glucose metabolism, strong pan-PI3K inhibitors raise safety concerns.

Subtype-selective inhibitors have been developed recently to lower toxicity. Specially authorized by the FDA in 2019 for use in conjunction with fulvestrant in hormone receptor-positive, HER2-negative metastatic breast cancer patients harboring PIK3CA mutations, Alpelisib is a selective inhibitor targeting the p110α catalytic subunit encoded by PIK3CA. With a notable decrease of 35% in the probability of disease progression or mortality, clinical studies revealed a progression-free survival (PFS) of 11 months in patients receiving Alpelisib vs 5.7 months in the placebo group.

References:

Adimonye A, Stankiewicz E, Kudahetti S, et al. Analysis of the PI3K-AKT-mTOR pathway in penile cancer: evaluation of a therapeutically targetable pathway. Oncotarget. 2018;9(22):16074-16086.
Hillmann P, Fabbro D. PI3K/mTOR Pathway Inhibition: Opportunities in Oncology and Rare Genetic Diseases. Int J Mol Sci. 2019;20(22):5792. Published 2019 Nov 18.
De Santis MC, Gulluni F, Campa CC, et al. Targeting PI3K signaling in cancer: Challenges and advances. Biochim Biophys Acta Rev Cancer. 2019;1871(2):361-366.
Glaviano A, Foo ASC, Lam HY, et al. PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer. Mol Cancer. 2023;22(1):138.

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