Pharmacodynamic activity of the AKT inhibitor AZD5363 in patients with advanced solid tumors.

2541 Background: AZD5363 is an ATP competitive small molecule inhibitor of AKT1, AKT2 and AKT3 and is currently in phase 1 and 2 clinical trials in breast, gynaecological and prostate cancer. In pre-clinical tumour xenograft models, AZD5363 inhibited the phosphorylation of AKT substrates PRAS40 and GSK3β in tumour tissue. Methods: Tumour biopsies were obtained from patients with advanced solid tumours in Western and Japanese phase 1 studies. Pharmacodynamic activity of AZD5363 in formalin fixed paraffin embedded tumour tissue was measured by immunohistochemistry (IHC) for total and phospho-AKT, phospho-PRAS40 and phospho-GSK3β using commercially available antibodies. IHC was quantified by H-score (sum of % tumour cells with 0=negative; 1=weak; 2=moderate; 3=strong staining) based on the results from 3 sections for each antibody. Inhibition of PRAS40 phosphorylation in hair follicles obtained 4 hours after dosing was measured by immunofluorescence and quantified by image analysis. Results: Paired tumour bi...