Dual targeting of the Akt/mTOR signaling pathway inhibits castration-resistant prostate cancer in a genetically engineered mouse model.
Dual targeting of the Akt/mTOR signaling pathway inhibits castration-resistant prostate cancer in a genetically engineered mouse model.
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DOI：
10.1158/0008-5472.can-12-0283
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发表时间：
2012-09-01
期刊：
影响因子：
11.2
通讯作者：
Abate-Shen C
中科院分区：
文献类型：
--
作者：
Floc'h N;Kinkade CW;Kobayashi T;Aytes A;Lefebvre C;Mitrofanova A;Cardiff RD;Califano A;Shen MM;Abate-Shen C
虽然临床上局限性前列腺癌的预后现在是有利的，但对于去势抵抗性前列腺癌仍然没有治愈性治疗，因此仍然是致命的。在这项研究中，我们研究了一种治疗去势抵抗性前列腺癌的新治疗方法，该方法涉及双重靶向疾病中经常失调的主要信号通路。我们发现，Akt和mTOR信号通路与其各自的抑制剂MK-2206和地磷莫司（MK-8669）的双重靶向作用，在临床前研究中使用该疾病的精细基因工程小鼠模型，在体内抑制去势抵抗性前列腺癌方面非常有效。联合治疗的有效性与其作为单一药物的有限有效性形成对比，因为单独递送MK-2206或MK-8669在体内对总体肿瘤表型具有适度影响。在人前列腺癌细胞系中，尽管不是在小鼠模型中，MK-2206和地磷莫司（MK-8669）的协同作用部分是由于限制Akt的mTORC 2反馈激活。此外，这些药物的作用是通过视网膜母细胞瘤（RB）途径抑制细胞增殖介导的。我们的研究结果表明，使用MK-2206和地磷莫司（MK-8669）双重靶向Akt和mTOR信号通路可能有效治疗去势抵抗性前列腺癌，特别是RB通路活性失调的患者。
While the prognosis for clinically localized prostate cancer is now favorable, there are still no curative treatments for castration-resistant prostate cancer and, therefore, remains fatal. In this study, we investigate a new therapeutic approach for treatment of castration-resistant prostate cancer, which involves dual targeting of a major signaling pathway that is frequently deregulated in the disease. We found that dual targeting of the Akt and mTOR signaling pathways with their respective inhibitors, MK-2206 and ridaforolimus (MK-8669), is highly effective for inhibiting castration-resistant prostate cancer in preclinical studies in vivo using a refined genetically-engineered mouse model of the disease. The efficacy of the combination treatment contrasts with their limited efficacy as single agents, since delivery of MK-2206 or MK-8669 individually had a modest impact in vivo on the overall tumor phenotype. In human prostate cancer cell lines, although not in the mouse model, the synergistic actions of MK-2206 and ridaforolimus (MK-8669) are due in part to limiting the mTORC2-feedback activation of Akt. Moreover, the effects of these drugs are mediated by inhibition of cellular proliferation via the retinoblastoma (RB) pathway. Our findings suggest that dual targeting the Akt and mTOR signaling pathways using MK-2206 and ridaforolimus (MK-8669) may be effective for treatment of castration-resistant prostate cancer, particularly for patients with deregulated RB pathway activity.