Antitumor Effects of Carnertinib in Castration Resistant Prostate Cancer Models: A Comparative Study With Erlotinib
Antitumor Effects of Carnertinib in Castration Resistant Prostate Cancer Models: A Comparative Study With Erlotinib
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DOI：
10.1002/pros.21363
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发表时间：
2011-10-01
期刊：
影响因子：
2.8
通讯作者：
Festuccia, Claudio
中科院分区：
文献类型：
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作者：
Gravina, Giovanni Luca;Marampon, Francesco;Festuccia, Claudio
背景和目的。虽然临床前结果表明，erb-B1或erb-B2的抑制可以是去势抵抗性前列腺癌（CRPC）的有用工具，但这两种抑制剂都没有表现出对这类患者的益处。在这里，我们比较了厄洛替尼（一种特异性EGFR抑制剂）与Carnertinib（一种口服泛erbB受体抑制剂）在一组激素敏感和非依赖性前列腺癌细胞系中的作用。将在体外评价厄洛替尼和卡奈替尼治疗后增殖率、细胞周期和细胞凋亡的变化。使用在裸鼠中生长的CRPC、22 rv 1（AR表达）和PC 3（AR阴性）细胞系的两种模型进行体内实验。携带22 rv 1细胞的完整裸鼠也接受了比卡鲁胺（BCLT）与抗靶向药物的联合给药。在这里，我们发现厄洛替尼和卡奈替尼的有效性与Her 2的表达和活化水平正相关，而厄洛替尼的有效性受EGFR/Her 2比率的影响，当EGFR水平显著高于Her 2时，厄洛替尼的有效性更高。总体而言，体外carnertinib疗效高于厄洛替尼观察到的疗效。厄洛替尼和雄激素剥夺治疗或BCLT之间的组合显示，与单一治疗相比，没有显着的效果，而carnertinib在任何抗激素操作的存在下是积极的。当我们与CRPC细胞中明显的作用相比时，厄洛替尼在雄激素敏感性PCa细胞中的疗效更高，而卡奈替尼的疗效可能在Her 2过表达AR+ CRPC模型中具有治疗意义，并与激素操作相结合。前列腺71：1481-1491，2011。(C)2011 Wiley-Liss，Inc.
BACKGROUND AND PURPOSE. Although preclinical results suggest that the inhibition of erb-B1 or erb-B2 can be an useful tool to castration resistant prostate cancer (CRPC), neither inhibitor demonstrated to provide benefit in this category of patient. Here, we compared the effects of erlotinib, a specific EGFR inhibitor, with those observed with Carnertinib, an orally available pan-erbB receptor inhibitor, in a wide panel of hormone sensitive and independent prostate cancer cell lines.MATERIALS AND METHODS. Variation in proliferation rate, cell cycle, and apoptosis after erlotinib and carnertinib treatments will be evaluated in vitro. In vivo experiments were performed using two models of CRPC, 22rv1 (AR expressing), and PC3 (AR negative) cell lines grown in nude mice. Intact nude mice bearing 22rv1 cells also received bicalutamide (BCLT) in combination with anti-target agents.RESULTS. Here, we found that Erlotinib and carnertinib effectiveness was positively related to expression and activation levels of Her2, whereas erlotinib effectiveness was influenced to the EGFR/Her2 ratio resulting more effective when EGFR levels were significantly higher of Her2. Overall, in vitro carnertinib efficacy was higher than those observed with erlotinib. The combination between erlotinib and androgen deprivation therapy or BCLT showed no significant effects when compared to single treatments whereas carnertinib was active in presence of any anti-hormone manipulation.CONCLUSIONS. Erlotinib efficacy was higher in androgen-sensitive PCa cells when we compare to the effects evident in CRPC cells, whereas the carnertinib efficacy may have therapeutical significance in Her2 overexpressing AR+ CRPC models in combination with hormone manipulation. Prostate 71: 1481-1491, 2011. (C) 2011 Wiley-Liss, Inc.