Preclinical testing of PI3K/AKT/mTOR signaling inhibitors in a mouse model of ovarian endometrioid adenocarcinoma.
Preclinical testing of PI3K/AKT/mTOR signaling inhibitors in a mouse model of ovarian endometrioid adenocarcinoma.
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DOI：
10.1158/1078-0432.ccr-11-1388
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发表时间：
2011-12-01
期刊：
影响因子：
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通讯作者：
Cho KR
中科院分区：
文献类型：
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作者：
Wu R;Hu TC;Rehemtulla A;Fearon ER;Cho KR
卵巢癌的基因工程小鼠(GEM)模型与人类肿瘤模型非常相似，可能是新疗法临床前测试的宝贵工具。我们研究了由规范的WNT和PI3K/AKT/mTOR信号通路的条件性失调引起的小鼠卵巢子宫内膜样腺癌(OEA)，以研究它们对常规化疗药物和mTOR或AKT抑制剂的反应。将表达Cre重组酶的重组腺病毒(AdCre)注射到Apcflx/FLOX；Ptenflx/FLOX小鼠的卵巢囊内，诱导OEA。荷瘤小鼠或小鼠OEA来源的细胞系用顺铂和紫杉醇、mTOR抑制剂雷帕霉素、AKT抑制剂API-2或Perifosine处理。通过肿瘤体积和生物发光成像监测体内治疗效果，通过WST-1增殖试验监测体外治疗效果，通过免疫印迹和免疫染色检测PI3K/AKT/mTOR信号通路成分的水平和磷酸化状态。小鼠在注射AdCre后3周内出现OEA，并且在此之前没有出现子宫内膜异位症。在体内，OEA对顺铂+紫杉醇、雷帕霉素和AKT抑制剂有反应。体外研究表明，对mTOR和AKT抑制剂的反应依赖于PI3K/AKT/mTOR信号转导状态，而不是常规的细胞毒药物。APC−/PTEN−肿瘤细胞中AKT的抑制可导致ERK信号的代偿性上调。这些研究表明，这种卵巢癌GEM模型可用于新型PI3K/AKT/mTOR信号转导抑制剂的临床前测试，并为信号转导的代偿性研究提供证据，提示对于PI3K/AKT/mTOR信号活化的卵巢癌，多药靶向治疗将比单一药物靶向治疗更有效。
Genetically engineered mouse (GEM) models of ovarian cancer that closely recapitulate their human tumor counterparts may be invaluable tools for preclinical testing of novel therapeutics. We studied murine ovarian endometrioid adenocarcinomas (OEAs) arising from conditional dysregulation of canonical WNT and PI3K/AKT/mTOR pathway signaling to investigate their response to conventional chemotherapeutic drugs and mTOR or AKT inhibitors. OEAs were induced by injection of adenovirus expressing Cre recombinase (AdCre) into the ovarian bursae of Apcflox/flox;Ptenflox/flox mice. Tumor-bearing mice or murine OEA-derived cell lines were treated with cisplatin and paclitaxel, mTOR inhibitor rapamycin, or AKT inhibitors API-2 or perifosine. Treatment effects were monitored in vivo by tumor volume and bioluminescence imaging, in vitro by WST-1 proliferation assays, and in OEA tissues and cells by immunoblotting and immunostaining for levels and phosphorylation status of PI3K/AKT/mTOR signaling pathway components. Murine OEAs developed within 3 weeks of AdCre injection and were not preceded by endometriosis. OEAs responded to cisplatin + paclitaxel, rapamycin, and AKT inhibitors in vivo. In vitro studies showed that response to mTOR and AKT inhibitors, but not conventional cytotoxic drugs, was dependent on the status of PI3K/AKT/mTOR signaling. AKT inhibition in APC−/PTEN− tumor cells resulted in compensatory up-regulation of ERK signaling. The studies demonstrate the utility of this GEM model of ovarian cancer for pre-clinical testing of novel PI3K/AKT/mTOR signaling inhibitors and provide evidence for compensatory signaling, suggesting that multiple rather than single agent targeted therapy will be more efficacious for treating ovarian cancers with activated PI3K/AKT/mTOR signaling.