The phosphatidylinositol 3-kinase (PI3K) AKT pathway is frequently activated in human cancers. 1 PI3K catalyzes the synthesis of phosphorylated phosphoinositides, resulting in AKT1 activation. PI3K is counteracted by the phosphatase PTEN, which is often inactivated in prostate cancer. In prostate cancer, inactivation of PTEN is associated with advanced stage and grade, and appears to be more common in late-stage disease. 2,3 Recently, a transforming mutation in the pleckstrin homology domain of AKT1 was described in human breast, colon and ovarian cancer. 4 The G > A mutation at nucleotide 49 results in a glutamic acid to lysine substitution at amino acid 17 (E17K) and leads to a PI3K-independent activation of AKT1. The E17K substitution in AKT1 has been confirmed by others in breast cancer, and recently it has also been identified in squamous cell carcinoma of the lung. 5,6 We identified the E17K substitution in 1 of 92 clinical prostate cancer samples (Fig. 1a). The prostate cancer samples sequenced were lymph node metastases (n 5 13) or transurethral resections of the prostate (TURP) (n 5 79). All lymph node metastases were without prior treatment. Over 60% of the TURP samples were taken under endocrine therapy, indicating that the majority of patients had late-stage disease.
Array-based comparative genomic hybridization of the tumor with the E17K substitution showed a chromosome composition characteristic for prostate cancer, including deletion of 8p and 16q (Fig. 1b). PTEN was not inactivated by deletion (Fig. 1b) or point mutation, and the sequences of the mutational hotspots in the catalytic subunit of PI3K were wild-type. Moreover, like the majority of prostate cancers, the tumor