mTOR inhibition elicits a dramatic response in PI3K-dependent colon cancers.
mTOR inhibition elicits a dramatic response in PI3K-dependent colon cancers.
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DOI：
10.1371/journal.pone.0060709
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Halberg RB
中科院分区：
文献类型：
--
作者：
Deming DA;Leystra AA;Farhoud M;Nettekoven L;Clipson L;Albrecht D;Washington MK;Sullivan R;Weichert JP;Halberg RB
磷脂酰肌醇-3-激酶（PI 3 K）信号传导通路对于多种细胞功能（包括代谢、增殖、血管生成和凋亡）至关重要，并且是人类癌症中最常见的改变通路。最近，我们开发了一种新的结肠癌小鼠模型，其中肿瘤由显性活性PI 3 K（FC PIK 3ca *）引发。这些小鼠中的癌症是近端结肠的中度分化的侵袭性粘液腺癌，其在50天龄时发展。有趣的是，这些癌症的形成没有良性中介或异常WNT信号传导，表明肿瘤发生的非经典机制。由于这些肿瘤依赖于PI 3 K通路，我们研究了通过用雷帕霉素（一种mTOR抑制剂）靶向该通路的肿瘤应答的潜力。将一组FC PIK 3ca * 小鼠用6 mg/kg/天剂量的雷帕霉素或安慰剂处理14天。FDG双杂交PET/CT成像显示雷帕霉素组中显著的肿瘤反应，这在尸检时得到证实。用雷帕霉素治疗后剩余的肿瘤组织表现出增加的pERK 1/2或持续磷酸化的核糖体蛋白S6（pS 6），表明潜在的耐药机制。这种独特的模型将进一步加深我们对人类疾病的理解，并通过药理学筛选和生物标志物鉴定促进治疗方法的开发。
The phosphatidylinositide-3-kinase (PI3K) signaling pathway is critical for multiple cellular functions including metabolism, proliferation, angiogenesis, and apoptosis, and is the most commonly altered pathway in human cancers. Recently, we developed a novel mouse model of colon cancer in which tumors are initiated by a dominant active PI3K (FC PIK3ca*). The cancers in these mice are moderately differentiated invasive mucinous adenocarcinomas of the proximal colon that develop by 50 days of age. Interestingly, these cancers form without a benign intermediary or aberrant WNT signaling, indicating a non-canonical mechanism of tumorigenesis. Since these tumors are dependent upon the PI3K pathway, we investigated the potential for tumor response by the targeting of this pathway with rapamycin, an mTOR inhibitor. A cohort of FC PIK3ca* mice were treated with rapamycin at a dose of 6 mg/kg/day or placebo for 14 days. FDG dual hybrid PET/CT imaging demonstrated a dramatic tumor response in the rapamycin arm and this was confirmed on necropsy. The tumor tissue remaining after treatment with rapamycin demonstrated increased pERK1/2 or persistent phosphorylated ribosomal protein S6 (pS6), indicating potential resistance mechanisms. This unique model will further our understanding of human disease and facilitate the development of therapeutics through pharmacologic screening and biomarker identification.
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有效使用 PI3K 和 MEK 抑制剂治疗突变型 Kras G12D 和 PIK3CA H1047R 小鼠肺癌。
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
5.7
作者：
Pal SK;Figlin RA;Reckamp K
通讯作者：
Reckamp K
影响因子：
4.8
作者：
Saam, JR;Gordon, JI
通讯作者：
Gordon, JI
影响因子：
64.5
作者：
CHUNG, J;KUO, CJ;BLENIS, J
通讯作者：
BLENIS, J
影响因子：
45.3
作者：
Allegra, Carmen J.;Jessup, J. Milburn;Schilsky, Richard L.
通讯作者：
Schilsky, Richard L.