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

PIK3CA H1047R is a prominent hotspot mutation located in the kinase domain (exon 20) of the PIK3CA gene, which encodes the p110α catalytic subunit of Phosphoinositide 3-kinase (PI3K) (OncoKB, 2024). This mutation induces a gain-of-function by enhancing the enzyme's affinity for the plasma membrane, leading to constitutive activation of the PI3K/AKT/mTOR signaling pathway (NIH, 2024). Such aberrant signaling is a major driver of oncogenesis, promoting uncontrolled cell growth, survival, and metabolic reprogramming in various solid tumors (PatSnap, 2024). It is particularly prevalent in breast, colorectal, and endometrial cancers, where it often correlates with resistance to standard treatments like endocrine therapy and HER2-targeted agents (NIH, 2024). Clinically, the H1047R mutation serves as a critical biomarker for selecting patients for PI3Kα-targeted therapies, such as alpelisib and inavolisib (NIH, 2024). A significant challenge in targeting this mutant is the on-target toxicity associated with inhibiting wild-type PI3Kα, which frequently results in systemic hyperglycemia (ACS, 2024). Consequently, current drug development is focused on mutant-selective inhibitors that specifically target the H1047R variant while sparing wild-type activity to improve the therapeutic index (ACS, 2024).

Other names

p110α H1047RPI3Kα H1047RPhosphoinositide-3-kinase catalytic subunit alpha H1047RPIK3CA exon 20 mutationp.H1047R mutant p110α

Inhibition of the catalytic activity of the p110α subunit, preventing the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3), thereby suppressing the PI3K/AKT/mTOR signaling pathway (NIH, 2024; PatSnap, 2024).