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 biopsies at baseline and after approximately 2 weeks dosing were obtained from patients on continuous and intermittent dosing schedules. Inhibition of GSK3β and PRAS40 phosphorylation of >30% or >50% respectively was seen in 4/7 (GSK3β) and 2/8 (PRAS40) tumours at tolerated doses of AZD5363. Phospho-AKT was increased in 4/7 (AKT-Thr308) and 4/5 (AKT-Ser473) tumours commensurate with the mechanism of action of AZD5363. Hair follicle PRAS40 phosphorylation was reduced by >50% in 22/71 patients and showed evidence of an exposure related response with an IC50 of 2μM total plasma concentration. Blood glucose also demonstrated an exposure response relationship with maximum glucose concentration correlating with drug plasma Cmax. Conclusions: Inhibition of AKT substrate phosphorylation in tumour biopsies from advanced cancer patients with a range of solid tumours was qualitatively comparable to that observed in preclinical models showing tumour growth inhibition at clinically achievable exposures. Clinical trial information: NCT01226316; NCT01353781.