{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPIK3CA encodes the p110α catalytic subunit of class IA phosphoinositide 3‐kinase, a critical enzyme that phosphorylates membrane phosphatidylinositols to generate second messengers and thereby activate downstream AKT/mTOR signaling. Activating “hotspot” mutations—most notably within the helical (e.g. E542K, E545K) and kinase (e.g. H1047R) domains—enhance p110α’s lipid kinase activity. This aberrant activation promotes cell survival, proliferation, growth factor independence, and oncogenic transformation in diverse contexts. Detailed biochemical analyses, structural studies, and experimental models (including gene targeting in cell culture and mouse models) have demonstrated that these mutations disrupt inhibitory interactions with regulatory subunits and potentiate constitutive signal transduction, leading to enhanced phosphorylation of AKT and downstream effectors that regulate cell cycle and protein synthesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "31"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nClinically, mutant PIK3CA not only serves as a prognostic and predictive biomarker but also informs therapeutic strategies. Its presence has been linked to resistance to certain targeted agents—such as anti‐EGFR monoclonal antibodies in colorectal cancer and trastuzumab in breast cancer—while simultaneously identifying tumors that may be more responsive to PI3K, mTOR, or dual PI3K/mTOR inhibitors. In addition, its interaction with other pathway components (for example, the frequent mutual exclusivity with PTEN loss) highlights divergent molecular routes of tumor evolution. Beyond oncogenesis, post‐zygotic activating mutations in PIK3CA have been implicated in a spectrum of overgrowth and vascular malformation disorders, emphasizing the enzyme’s central role in regulating normal as well as aberrant cellular growth."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "32", "end_ref": "43"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nThese cumulative insights have spurred the development of next‐generation therapies, including isoform–selective inhibitors and combination regimens (for instance, with CDK4/6 or MEK inhibitors) designed to overcome intrinsic or adaptive resistance. Further structural and functional characterization of PIK3CA mutations continues to inform precision medicine approaches—not only in oncology but also in congenital overgrowth syndromes—by pinpointing critical vulnerabilities within the PI3K/AKT/mTOR axis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "44"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "C L Carpenter, B C Duckworth, K R Auger, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Purification and characterization of phosphoinositide 3-kinase from rat liver."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (1990)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "2174051"}], "href": "https://pubmed.ncbi.nlm.nih.gov/2174051"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Kurtis E Bachman, Pedram Argani, Yardena Samuels, et al. 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