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

Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) with the H1047R mutation is a prominent oncogenic driver in human cancers [1, 4, 7]. This specific missense mutation occurs in the kinase domain (exon 21) and results in a gain-of-function that constitutively activates the PI3K/AKT/mTOR signaling pathway [7, 10]. The H1047R variant promotes increased lipid kinase activity and plasma membrane recruitment, leading to enhanced cell proliferation, survival, and metabolic reprogramming [1, 9]. It is particularly prevalent in hormone receptor-positive, HER2-negative breast cancers, as well as colorectal and endometrial malignancies [1, 7, 8]. Clinical management often involves the use of PI3K inhibitors, such as alpelisib, which are specifically indicated for patients harboring PIK3CA mutations [3, 4, 7]. However, a significant challenge in targeting this molecule is the on-target toxicity of hyperglycemia, caused by the inhibition of wild-type PI3Kα's role in insulin signaling [3, 12]. Consequently, recent drug development has shifted toward mutant-selective inhibitors to improve the therapeutic index and patient outcomes [1, 3, 12].

Other names

p110 alpha H1047R [1, 7]PI3K alpha H1047R [3]PIK3CA p.His1047Arg [11]Phosphoinositide-3-kinase catalytic subunit alpha H1047R [1, 7]

Inhibition of the PI3K/AKT/mTOR signaling pathway by binding to the ATP-binding pocket of the PI3K enzyme, thereby preventing phosphorylation of downstream targets and inducing apoptosis in mutant cells [1, 3].