转化生长因子-β受体I抑制剂在晚期前列腺癌临床前模型中增强对恩杂鲁胺的反应。
TGF-β receptor I inhibitor enhances response to enzalutamide in a pre-clinical model of advanced prostate cancer.
作者信息
Paller Channing, Pu Hong, Begemann Diane E, Wade Cameron A, Hensley Patrick J, Kyprianou Natasha
机构信息
The Johns Hopkins Kimmel Cancer Center and Department of Medicine, Johns Hopkins University, Baltimore, Maryland.
Department of Urology, University of Kentucky College of Medicine, Lexington, Kentucky.
出版信息
Prostate. 2019 Jan;79(1):31-43. doi: 10.1002/pros.23708. Epub 2018 Aug 28.
BACKGROUND
Prostate cancer progression is navigated by the androgen receptor (AR) and transforming-growth factor-β (TGF-β) signaling. We previously demonstrated that aberrant TGF-β signaling accelerates prostate tumor progression in a transgenic mouse model of prostate cancer via effects on epithelial-mesenchymal transition (EMT), driving castration-resistant prostate cancer (CRPC).
METHODS
This study examined the antitumor effect of the combination of TGF-β receptor I (TβRI) inhibitor, galunisertib, and FDA-approved antiandrogen enzalutamide, in our pre-clinical model. Age-matched genotypically characterized DNTGFβRII male mice were treated with either galunisertib and enzalutamide, in combination or as single agents in three "mini"-trials and the effects on tumor growth, phenotypic EMT, and actin cytoskeleton were evaluated.
RESULTS
Galunisertib in combination with enzalutamide significantly suppressed prostate tumor growth, by increasing apoptosis and decreasing cell proliferation of tumor cell populations compared to the inhibitor as a monotherapy (P < 0.05). The combination treatment dramatically reduced cofilin levels, actin cytoskeleton regulator, compared to single agents. Treatment with galunisertib targeted nuclear Smad4 protein (intracellular TGF-β effector), but had no effect on nuclear AR. Consequential to TGF-β inhibition there was an EMT reversion to mesenchymal-epithelial transition (MET) and re-differentiation of prostate tumors. Elevated intratumoral TGF-β1 ligand, in response to galunisertib, was blocked by enzalutamide.
CONCLUSION
Our results provide novel insights into the therapeutic value of targeting TGF-β signaling to overcome resistance to enzalutamide in prostate cancer by phenotypic reprogramming of EMT towards tumor re-differentiation and cytoskeleton remodeling. This translational work is significant in sequencing TGF-β blockade and antiandrogens to optimize therapeutic response in CRPC.
背景
前列腺癌的进展受雄激素受体（AR）和转化生长因子-β（TGF-β）信号传导调控。我们之前证明，在前列腺癌转基因小鼠模型中，异常的TGF-β信号传导通过影响上皮-间质转化（EMT）加速前列腺肿瘤进展，导致去势抵抗性前列腺癌（CRPC）。
方法
本研究在我们的临床前模型中检测了TGF-β受体I（TβRI）抑制剂加鲁尼西替和FDA批准的抗雄激素恩杂鲁胺联合使用的抗肿瘤效果。将年龄匹配、基因特征明确的DNTGFβRII雄性小鼠在三项“小型”试验中联合或单独使用加鲁尼西替和恩杂鲁胺进行治疗，并评估对肿瘤生长、表型EMT和肌动蛋白细胞骨架的影响。
结果
与单一疗法相比，加鲁尼西替与恩杂鲁胺联合使用通过增加肿瘤细胞群体的凋亡和减少细胞增殖，显著抑制前列腺肿瘤生长（P < 0.05）。与单一药物相比，联合治疗显著降低了肌动蛋白细胞骨架调节因子丝切蛋白的水平。加鲁尼西替治疗靶向核Smad4蛋白（细胞内TGF-β效应器），但对核AR没有影响。由于TGF-β抑制，EMT逆转至间质-上皮转化（MET），前列腺肿瘤重新分化。恩杂鲁胺可阻断加鲁尼西替引起的肿瘤内TGF-β1配体升高。
结论
我们的结果为靶向TGF-β信号传导的治疗价值提供了新的见解，即通过将EMT表型重编程为肿瘤重新分化和细胞骨架重塑来克服前列腺癌对恩杂鲁胺的耐药性。这项转化研究对于确定TGF-β阻断和抗雄激素的顺序以优化CRPC的治疗反应具有重要意义。
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