GSK690693 delays tumor onset and progression in genetically defined mouse models expressing activated Akt.
GSK690693 delays tumor onset and progression in genetically defined mouse models expressing activated Akt.
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DOI：
10.1158/1078-0432.ccr-09-1026
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发表时间：
2010-01-15
期刊：
影响因子：
--
通讯作者：
Testa JR
中科院分区：
文献类型：
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作者：
Altomare DA;Zhang L;Deng J;Di Cristofano A;Klein-Szanto AJ;Kumar R;Testa JR
AKT在调节肿瘤细胞存活和细胞周期进程中起着核心作用，被认为是一个有前途的治疗靶点。我们使用遗传学定义的小鼠模型，这些小鼠模型发展出表现出激活的Akt的自发性肿瘤，以确定GSK 690693对Akt的抑制是否有效治疗癌症。该项目的广泛、长期目标是使用具有精确定义的遗传病变的临床前癌症模型来阐明GSK 690693靶向Akt的疗效。我们测试了GSK 690693在发生淋巴瘤的Lck-MyrAkt 2转基因小鼠、发生子宫内膜肿瘤的杂合Pten+/−敲除小鼠和发生卵巢癌的TgMISIIR-TAg-DR 26小鼠中的体内作用，所有这些小鼠都表现出Akt的过度激活。除了标准疾病发作和组织学之外，通过免疫组织化学检查治疗的动物中产生的肿瘤，以验证相对于安慰剂治疗的小鼠下调的Akt信号传导。如果可能，通过标准增殖和凋亡测定以及使用各种磷酸化特异性抗体的免疫印迹，在肿瘤细胞培养物中评价药物反应。GSK 690693表现出疗效，与所涉及的Akt激活机制无关。有趣的是，GSK 690693在表达膜结合的、组成型活性形式的Akt的Lck-MyrAkt 2小鼠中延迟肿瘤进展方面最有效。肿瘤和原代细胞培养物均显示Akt途径的下调，凋亡增加，主要是细胞增殖减少。这些结果表明，GSK 690693或其他AKT抑制剂可能在具有过度活化的AKT和/或依赖于AKT信号传导的肿瘤进展的人类癌症中具有治疗功效。
AKT plays a central role in regulating tumor cell survival and cell cycle progression, and is regarded as a promising therapeutic target. We used genetically-defined mouse models that develop spontaneous tumors exhibiting activated Akt to determine if Akt inhibition by GSK690693 is effective in the treatment of cancer. The broad, long-term objective of this project was to use preclinical cancer models with precisely defined genetic lesions to elucidate the efficacy of targeting Akt with GSK690693. We tested the in vivo effects of GSK690693 in Lck-MyrAkt2 transgenic mice that develop lymphomas, heterozygous Pten+/− knockout mice that exhibit endometrial tumors, and TgMISIIR-TAg-DR26 mice that develop ovarian carcinomas, all of which exhibit hyperactivation of Akt. In addition to standard disease onset and histology, tumors arising in treated animals were examined by immunohistochemistry to verify down regulated Akt signaling relative to placebo-treated mice. When possible, drug response was evaluated in tumor cell cultures by standard proliferation and apoptosis assays and by immunoblotting with various phospho-specific antibodies. GSK690693 exhibited efficacy irrespective of the mechanism of Akt activation involved. Interestingly, GSK690693 was most effective in delaying tumor progression in Lck-MyrAkt2 mice expressing a membrane-bound, constitutively active form of Akt. Both tumors and primary cell cultures displayed down regulation of the Akt pathway, increased apoptosis and primarily decreased cell proliferation. These results suggest that GSK690693 or other AKT inhibitors might have therapeutic efficacy in human cancers with hyperactivated AKT and/or a dependence on AKT signaling for tumor progression.