Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha (PI3Kα) H1047R mutant (PI3Kα H1047R)

The PIK3CA H1047R mutant is a specific, highly prevalent hotspot mutation located in the kinase domain of the p110α catalytic subunit of phosphoinositide 3-kinase alpha (PI3Kα) (UniProt P42336). This mutation results in the constitutive activation of the PI3K/AKT/mTOR signaling pathway, which is a master regulator of essential cellular processes such as growth, proliferation, survival, and metabolism (OncoKB). Mechanistically, the H1047R substitution enhances the enzyme's affinity for the plasma membrane, leading to hyperactive lipid kinase activity and subsequent oncogenic transformation (PMID: 17376864). It is one of the most common mutations in human cancers, particularly in hormone receptor-positive, HER2-negative breast cancer, as well as colorectal, endometrial, and ovarian malignancies (PMID: 27126994). Therapeutic strategies focus on inhibiting this hyperactive kinase to disrupt downstream signaling and inhibit tumor progression. Drugs like alpelisib and inavolisib have been developed as isoform-selective inhibitors to target PI3Kα in patients harboring these mutations (FDA). A significant challenge in targeting PI3Kα is the management of on-target toxicities, most notably hyperglycemia, which arises from the inhibition of wild-type PI3Kα involved in insulin signaling. Consequently, current research is directed toward developing next-generation mutant-selective and allosteric inhibitors, such as LOXO-783 and STX-478, that specifically target the H1047R variant while sparing the wild-type protein's metabolic functions (ACS Central Science).

Other names

p110α H1047RPIK3CA H1047RPhosphoinositide 3-kinase alpha H1047Rp110-alpha H1047RPIK3CA p.H1047R

Selective inhibition of the p110α catalytic subunit of phosphoinositide 3-kinase, preventing the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3) and thereby suppressing the PI3K/AKT/mTOR signaling pathway.