Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha E542K and E545K mutants (PI3Kα E542K/E545K)

Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha (PI3Kα) is a critical lipid kinase that converts PIP2 to PIP3, initiating the PI3K/AKT/mTOR signaling cascade responsible for cell growth, survival, and metabolism [1, 2]. The E542K and E545K mutations are common oncogenic hotspot alterations located in the helical domain (exon 9) of the PIK3CA gene [2, 3]. These specific mutations disrupt the inhibitory interaction between the p110α catalytic subunit and the nSH2 domain of the p85 regulatory subunit, leading to constitutive, growth factor-independent activation of the enzyme [4]. This hyperactivation is a major driver in several cancers, particularly hormone receptor-positive (HR+) breast cancer, where it contributes to endocrine therapy resistance [3, 5]. Therapeutic targeting of these mutants is primarily achieved through PI3Kα-selective inhibitors like alpelisib, which compete for the ATP-binding site to suppress downstream signaling [3]. However, because PI3Kα is essential for insulin signaling, its inhibition frequently results in systemic side effects such as hyperglycemia and hyperinsulinemia [5, 6]. Newer mutant-selective inhibitors like RLY-2608 are currently being developed to improve the therapeutic index by sparing wild-type PI3Kα activity in metabolic tissues [5]. Sources: [1] UniProt P42336; [2] Samuels et al., Science (2004); [3] André et al., NEJM (2019); [4] Miled et al., Science (2007); [5] Relay Therapeutics (2023); [6] Goncalves et al., Nature (2018).

Other names

PIK3CA E542KPIK3CA E545Kp110α helical domain mutantsPhosphoinositide-3-kinase catalytic subunit alpha E542K/E545KPIK3CA exon 9 mutants

ATP-competitive inhibition of the p110α catalytic subunit of phosphoinositide 3-kinase