Exceptional Response to AKT Inhibition in Patients with Breast Cancer and Germline PTEN Mutations

Cowden syndrome is an autosomal dominant genetic disease with an estimated incidence of one in 200,000. Affected individuals develop multiple systemic hamartomas and have a cumulative lifetime risk of breast cancer of 85%. Approximately 80% of patients with Cowden syndrome have a germline inactivating mutation in PTEN (10q23.3). PTEN acts as a tumor suppressor gene via numerous mechanisms, one of which is antagonizing the PI3K/AKT/mTOR signaling pathway by dephosphorylating phosphatidylinositol (3,4,5)-trisphosphate (PIP3). PIP3 functions as a secondary messenger in the PI3K pathway that binds and activates proteins that have a pleckstrin homology domain, such as AKT1, and triggers their activation and localization to the plasma membrane, promoting cellular proliferation and survival.