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p-AKT Protein Expression Predicts Response to AKT Inhibitor Combined with Docetaxel Therapy in Adenocarcinoma and
Hipacia Werneck Gomes1, Natalie L Lister1, Shivakumar Keerthikumar1,2,3
1Department of Anatomy and Developmental Biology, Prostate Cancer Research Group, Monash Biomedicine Discovery Institute, Cancer Program, Monash University, Clayton, Australia.
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.
Insights
Phospho-AKT (p-AKT) protein levels, not PTEN, may predict response to capivasertib and docetaxel combination therapy in prostate cancer. This combination shows promise for neuroendocrine prostate cancer, guiding future clinical trial patient selection.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Metastatic castration-resistant prostate cancer (mCRPC) treatments include docetaxel, with AKT inhibitors like capivasertib showing potential.
- PTEN loss is a theoretical biomarker for AKT inhibitor response, but clinical data are inconsistent.
- Identifying reliable biomarkers is crucial for optimizing AKT inhibitor therapy in prostate cancer.
Purpose of the Study:
- To identify predictive biomarkers for response to the combination of an AKT inhibitor (capivasertib) and docetaxel in prostate cancer.
- To investigate the role of PTEN and phosphorylated AKT (p-AKT) in predicting treatment efficacy.
- To explore the efficacy of this combination in different prostate cancer subtypes using patient-derived models.
Main Methods:
- Utilized 39 prostate cancer patient-derived xenografts (PDXs) with adenocarcinoma and neuroendocrine phenotypes.
- Assessed PTEN and p-AKT(Ser473) protein expression via immunostaining and performed targeted DNA sequencing.
- Evaluated drug effects in matching PDX-derived organoids using capivasertib and docetaxel in vitro.
Main Results:
- p-AKT protein expression varied widely and did not correlate with PTEN/PI3K/AKT mutations or PTEN protein levels.
- Neuroendocrine prostate cancer models exhibited higher p-AKT expression compared to adenocarcinomas.
- Synergistic growth inhibition was observed with capivasertib and docetaxel in organoids with a neuroendocrine phenotype and high p-AKT expression.
Conclusions:
- Preclinical data suggest p-AKT protein expression is a more reliable biomarker than PTEN for predicting response to capivasertib plus docetaxel.
- The combination therapy demonstrated efficacy in neuroendocrine prostate cancer models, particularly those with high p-AKT.
- These findings support refining patient selection for clinical trials based on p-AKT expression levels.
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