E545K

E545K is a missense mutation in the PIK3CA gene, which encodes the catalytic subunit p110α of phosphatidylinositol‑3‑kinase (PI3K). The mutation replaces the negatively charged glutamic acid (E) with a positively charged lysine (K) at amino acid position 545, located within the helical domain of the protein. This single amino acid change is one of the most common oncogenic alterations in PIK3CA and is classified as a hotspot mutation.

The E545K substitution stabilises the interaction between the catalytic and regulatory subunits of PI3K, promoting constitutive kinase activity in the absence of upstream signals. The resulting increase in phosphatidylinositol (3,4,5)-trisphosphate (PIP3) leads to activation of downstream effectors such as AKT and mTOR, driving cellular proliferation, survival, and metabolic reprogramming. Functional studies show that cells harbouring E545K have enhanced anchorage‑independent growth and tumorigenic potential in vivo.

Clinically, E545K is frequently detected in solid tumours, including breast, colorectal, uterine, endometrial, and cervical cancers, as well as in some cases of colorectal adenomas and invasive lobular carcinoma. Its presence is associated with aggressive tumour biology, higher tumour grade, and, in some reports, resistance to hormone therapy and anti‑HER2 therapies. Diagnostic testing routinely includes the E545K locus in targeted next‑generation sequencing panels for precision oncology.

Therapeutically, inhibitors that target PI3Kα, such as alpelisib, have shown efficacy in tumours with PIK3CA mutations including E545K. Combination strategies with CDK4/6 inhibitors, mTOR inhibitors, or endocrine agents are under investigation to overcome pathway feedback and resistance.