多西紫杉醇
前列腺癌
癌症
医学
前列腺
药理学
癌症研究
内科学
作者
Stefan A.J. Buck,A. Van Hemelryk,Corrina de Ridder,Debra Stuurman,Sigrun Erkens-Schulze,Sem Van 't Geloof,Wilma Teubel,Stijn L.W. Koolen,Elena S. Martens‐Uzunova,Martin E. van Royen,Ronald de Wit,Ron H.J. Mathijssen,Wytske M. van Weerden
出处
期刊:Molecular Cancer Therapeutics
[American Association for Cancer Research]
日期:2024-01-11
卷期号:: OF1-OF10
被引量:1
标识
DOI:10.1158/1535-7163.mct-23-0420
摘要
Resistance to taxane chemotherapy is frequently observed in metastatic prostate cancer. The androgen receptor (AR) is a major driver of prostate cancer and a key regulator of the G1-S cell cycle checkpoint, promoting cancer cell proliferation by irreversible passage to the S-phase. We hypothesized that AR signaling inhibitor (ARSi) darolutamide in combination with docetaxel could augment antitumor effect by impeding the proliferation of taxane-resistant cancer cells. We monitored cell viability in organoids, tumor volume and PSA secretion in patient-derived xenografts (PDXs) and analyzed cell cycle and signaling pathway alterations. Combination treatment increased anti-tumor effect in androgen-sensitive, AR-positive prostate cancer organoids and PDXs. Equally beneficial effects of darolutamide added to docetaxel were observed in a castration-resistant model, progressive on docetaxel, enzalutamide and cabazitaxel. In vitro studies showed that docetaxel treatment with simultaneous darolutamide resulted in a reduction of cells entering the S-phase in contrast to only docetaxel. Molecular analysis in the prostate cancer cell line LNCaP revealed an upregulation of Cyclin Dependent Kinase inhibitor p21, supporting blockade of S-phase entry and cell proliferation. Our results provide a preclinical support for combining taxanes and darolutamide as a multimodal treatment strategy in metastatic prostate cancer patients progressive on ARSi and taxane chemotherapy.
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