p-AKT Protein Expression Predicts Response to AKT Inhibitor Combined with Docetaxel Therapy in Adenocarcinoma and Neuroendocrine Prostate Cancer

PURPOSE: AKT inhibitors, such as capivasertib, have shown activity in specific patients with metastatic castration-resistant prostate cancer when combined with docetaxel although none have been approved. Although PTEN loss is often linked to AKT pathway activation and response to AKT inhibitors, clinical trials show no consistent association. This study uses patient-derived tumor models to identify biomarkers associated with an effective response to AKT inhibitor plus docetaxel. EXPERIMENTAL DESIGN: Targeted DNA sequencing and immunostaining for PTEN and phosphorylated AKT (p-AKT; Ser473) were assessed in 39 patient-derived xenografts (PDX) from patients with prostate cancer, including adenocarcinoma and neuroendocrine (NE) phenotypes. Matching PDX-derived organoids were used to evaluate the functional effects of capivasertib and docetaxel on in vitro tumor growth. RESULTS: p-AKT protein expression varied widely across PDX models and showed no correlation with PTEN/PI3K/AKT mutations or PTEN protein levels. NE tumors displayed higher p-AKT expression than adenocarcinomas. Knockdown of AKT1 in NE organoids increased sensitivity to docetaxel, whereas AKT1 overexpression decreased it. In three of seven organoids tested, the combination of capivasertib and docetaxel produced a synergistic effect, resulting in greater growth inhibition than either agent alone. These responsive organoids exhibited an NE phenotype and high p-AKT expression, consistent with a predictive response. CONCLUSIONS: Our preclinical findings indicate that p-AKT protein expression, rather than PTEN, may be a more reliable predictor of response to AKT inhibition combined with docetaxel. Using p-AKT as a parameter, we uncovered the efficacy of this combination in NE prostate cancer, highlighting the potential to refine patient selection criteria for future clinical trials.