Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha (p110α) H1047R (PIK3CA H1047R)

The Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha (p110α) H1047R is a gain-of-function missense mutation in the kinase domain of the PIK3CA gene, which encodes the p110α catalytic subunit of class IA PI3K, a lipid kinase that phosphorylates phosphatidylinositol 4,5-bisphosphate (PIP2) to generate the second messenger PIP3, thereby activating downstream effectors like Akt to promote cell survival, proliferation, migration, and metabolism. This H1047R mutation, one of the most common oncogenic alterations in PIK3CA, results in constitutive PI3K activation independent of upstream signals, leading to excessive PIP3 production, enhanced phosphorylation of Akt and MEK1/2, cytoskeletal reorganization (e.g., reduced F-actin polymerization and increased filopodia formation), and increased cell motility. It drives tumorigenesis across multiple cancers, including colorectal, breast, lung, ovarian, and gastric cancers, by conferring growth advantages such as transformation in vitro, metastasis in vivo (e.g., higher liver metastasis in colon cancer models), and resistance to apoptosis. Structurally, the mutation induces conformational changes that expose membrane-binding regions, enabling RAS-independent membrane localization and hyperactivation. Therapeutically, it is targeted by isoform-selective PI3Kα inhibitors like alpelisib (approved for PIK3CA-mutant breast cancer) and others such as A66 or MEN1611, which show preclinical sensitivity in H1047R models, though challenges include pathway reactivation and variable responses.

Other names

p110α H1047RPik3ca H1047R

PI3K inhibition, Akt inhibition, mTOR inhibition