Werneck Gomes Hipacia, Lister Natalie L, Keerthikumar Shivakumar, Niranjan Birunthi, Richards Michelle G, Ryan Andrew, Kwan Edmond M, Risbridger Gail P, Taylor Renea A
Department of Anatomy and Developmental Biology, Prostate Cancer Research Group, Monash Biomedicine Discovery Institute, Cancer Program, Monash University, Clayton, Australia.
Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Australia.
Clin Cancer Res. 2025 Jul 1;31(13):2727-2740. doi: 10.1158/1078-0432.CCR-24-3848.
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.
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.
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.
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.
AKT抑制剂，如卡匹西利，与多西他赛联合使用时，在特定转移性去势抵抗性前列腺癌患者中显示出活性，尽管尚无药物获批。虽然PTEN缺失常与AKT通路激活及对AKT抑制剂的反应相关，但临床试验并未显示出一致的关联。本研究使用患者来源的肿瘤模型来鉴定与AKT抑制剂加多西他赛有效反应相关的生物标志物。
对39例前列腺癌患者（包括腺癌和神经内分泌（NE）表型）来源的异种移植瘤（PDX）进行PTEN和磷酸化AKT（p-AKT；Ser473）的靶向DNA测序和免疫染色。使用匹配的PDX来源的类器官评估卡匹西利和多西他赛对体外肿瘤生长的功能影响。
p-AKT蛋白表达在PDX模型中差异很大，与PTEN/PI3K/AKT突变或PTEN蛋白水平无相关性。NE肿瘤的p-AKT表达高于腺癌。在NE类器官中敲低AKT1可增加对多西他赛的敏感性，而AKT1过表达则降低敏感性。在7个测试的类器官中，有3个显示卡匹西利和多西他赛联合使用产生协同效应，导致比单独使用任何一种药物更大的生长抑制。这些有反应的类器官表现出NE表型和高p-AKT表达，与预测反应一致。
我们的临床前研究结果表明，p-AKT蛋白表达而非PTEN可能是对AKT抑制联合多西他赛反应更可靠的预测指标。以p-AKT作为参数，我们发现了这种联合治疗在NE前列腺癌中的疗效，突出了为未来临床试验完善患者选择标准的潜力。
