Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha (PI3Kα) E545K mutant (PI3Kα E545K)

Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha (PI3Kα) E545K is a common oncogenic hotspot mutation located in the helical domain of the p110α protein [NIH, AACR]. This mutation involves a charge-reversal substitution (glutamic acid to lysine) that disrupts the inhibitory interaction between the catalytic subunit and its regulatory partner, p85α, leading to constitutive kinase activity [NIH, ResearchGate]. The resulting hyperactivation of the PI3K/AKT/mTOR signaling pathway drives essential processes in tumorigenesis, such as uncontrolled cell proliferation, enhanced survival, and metabolic reprogramming [NIH, PatSnap]. PI3Kα E545K is frequently found in various malignancies, including breast, colorectal, and endometrial cancers, and is often associated with resistance to endocrine therapies [OncoKB, NIH]. Therapeutic intervention primarily involves PI3K inhibitors like alpelisib and inavisib, which target the ATP-binding pocket of the enzyme [AACR, NIH]. However, because these drugs also inhibit wild-type PI3Kα, they are associated with significant metabolic side effects like hyperglycemia [NIH, The Innovation]. Emerging mutant-selective allosteric inhibitors, such as RLY-2608, are currently being developed to specifically target the conformational changes induced by the mutation, potentially offering improved efficacy and reduced toxicity [AACR, The Innovation].

Other names

PIK3CA E545Kp110α E545KPhosphoinositide 3-kinase alpha E545KPIK3CA exon 9 mutationE545K mutation

PI3Kα inhibitors typically act as ATP-competitive inhibitors that bind to the catalytic site of the p110α subunit, thereby preventing the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) into phosphatidylinositol 3,4,5-trisphosphate (PIP3) [NIH, AACR]. This blockade suppresses the activation of the AKT/mTOR signaling pathway, which is constitutively active in the presence of the E545K mutation [NIH, PatSnap].