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

PI3Kα H1047R is a gain-of-function mutant form of the p110α catalytic subunit of Phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K), encoded by the PIK3CA gene [1]. This specific mutation involves a substitution of histidine with arginine at position 1047 within the kinase domain, which leads to constitutive enzymatic activity and hyperactivation of the PI3K/AKT/mTOR signaling pathway [4]. It is one of the most frequent oncogenic "hotspot" mutations in human malignancies, particularly prevalent in hormone receptor-positive (HR+) breast cancer, colorectal cancer, and endometrial cancer [3, 5]. The mutation drives essential cellular processes such as growth, proliferation, and survival independent of external growth factor stimulation [1, 3]. In the clinical setting, this mutant is a primary target for PI3Kα-selective inhibitors like alpelisib, which was the first treatment approved specifically for PIK3CA-mutated advanced breast cancer [2]. A significant challenge in targeting this molecule is the metabolic side effect of hyperglycemia, caused by the concurrent inhibition of wild-type PI3Kα involved in insulin signaling [3]. Consequently, next-generation drug development is focused on mutant-selective inhibitors, such as RLY-2608 and STX-478, which aim to specifically target the H1047R variant while sparing the wild-type protein [3, 6]. These advancements aim to improve the therapeutic index by reducing systemic toxicities while maintaining potent anti-tumor activity [3]. References: [1] UniProt P42336; [2] FDA Piqray Approval (2019); [3] Cancer Discovery (2022, 12(7):1600-1618); [4] Mandelker et al. (2009) PNAS 106(39):16794-16798; [5] COSMIC Database; [6] Relay Therapeutics Pipeline (2024).

Other names

p110α H1047RPIK3CA H1047RPhosphoinositide 3-kinase alpha H1047RPI3K-alpha H1047R

Selective inhibition of the PI3K alpha catalytic subunit to block the PI3K/AKT/mTOR signaling pathway