Schneider Meike, Korzeniewski Nina, Merkle Konstanze, Schüler Julia, Grüllich Carsten, Hadaschik Boris, Hohenfellner Markus, Duensing Stefan
Department of Urology, University of Heidelberg School of Medicine, Heidelberg, Germany.
Molecular Urooncology, Department of Urology, University of Heidelberg School of Medicine, Heidelberg, Germany.
Urol Oncol. 2015 Feb;33(2):72.e1-7. doi: 10.1016/j.urolonc.2014.06.001. Epub 2014 Jul 2.
Novel therapeutic options beyond hormone ablation and chemotherapy are urgently needed for patients with advanced prostate cancer. Tyrosine kinase inhibitors (TKIs) are an attractive option as advanced prostate cancers show a highly altered phosphotyrosine proteome. However, despite favorable initial clinical results, the combination of the TKI dasatinib with docetaxel did not result in improved patient survival for reasons that are not known in detail.
The National Cancer Institute-Approved Oncology Drug Set II was used in a phenotypic drug screen to identify novel compounds with antineoplastic activity in prostate cancer cells. Validation experiments were carried out in vitro and in vivo.
We identified the TKI nilotinib as a novel compound with antineoplastic activity in hormone-refractory prostate cancer cells. However, further analyses revealed that treatment with nilotinib was associated with a significant up-regulation of the phospho-extracellular-signal-regulated kinases (ERK) survival signal. ERK blockade alone led to a significant antitumoral effect and enhanced the cytotoxicity of nilotinib when used in combination.
Our findings underscore that TKIs, such as nilotinib, have antitumoral activity in prostate cancer cells but that survival signals, such as ERK up-regulation, may mitigate their effectiveness. ERK blockade alone or in combination with TKIs may represent a promising therapeutic strategy in advanced prostate cancer.
晚期前列腺癌患者迫切需要激素消融和化疗以外的新型治疗选择。酪氨酸激酶抑制剂（TKIs）是一个有吸引力的选择，因为晚期前列腺癌显示出高度改变的磷酸酪氨酸蛋白质组。然而，尽管初始临床结果良好，但TKI达沙替尼与多西他赛联合使用并未改善患者生存率，其原因尚不清楚。
在表型药物筛选中使用美国国立癌症研究所批准的肿瘤学药物集II，以鉴定在前列腺癌细胞中具有抗肿瘤活性的新型化合物。在体外和体内进行验证实验。
我们鉴定出尼洛替尼是一种在激素难治性前列腺癌细胞中具有抗肿瘤活性的新型化合物。然而，进一步分析显示，用尼洛替尼治疗与磷酸化细胞外信号调节激酶（ERK）生存信号的显著上调有关。单独阻断ERK会产生显著的抗肿瘤作用，并在联合使用时增强尼洛替尼的细胞毒性。
我们的研究结果强调，像尼洛替尼这样的TKIs在前列腺癌细胞中具有抗肿瘤活性，但生存信号，如ERK上调，可能会削弱其有效性。单独或与TKIs联合阻断ERK可能是晚期前列腺癌一种有前景的治疗策略。
