The dual PI3K/mTOR inhibitor NVP-BEZ235 induces tumor regression in a genetically engineered mouse model of PIK3CA wild-type colorectal cancer.
The dual PI3K/mTOR inhibitor NVP-BEZ235 induces tumor regression in a genetically engineered mouse model of PIK3CA wild-type colorectal cancer.
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DOI：
10.1371/journal.pone.0025132
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Hung KE
中科院分区：
文献类型：
--
作者：
Roper J;Richardson MP;Wang WV;Richard LG;Chen W;Coffee EM;Sinnamon MJ;Lee L;Chen PC;Bronson RT;Martin ES;Hung KE
探讨PI3K/mTOR双抑制剂NVP-BEZ235治疗PIK3CA野生型结直肠癌（CRC）的体内外疗效。用NVP-BEZ235体外处理PIK3CA突变型和野生型人CRC细胞系，并评估其对增殖、凋亡和信号传导的影响。用NVP-BEZ235在体内治疗散发性野生型PIK3CA CRC的基因工程小鼠（GEM）模型中的结肠肿瘤。研究结果对宏观肿瘤生长/消退、增殖、凋亡、血管生成和信号传导的影响。NVP-BEZ235对结直肠癌细胞系的体外处理导致短暂的PI3K阻断，mTORC1/mTORC2信号持续下降，细胞活力相应下降（中位IC50 = 9.0-14.3 nM）。在配对的等基因结直肠癌细胞系中也观察到类似的效果，这些细胞系的差异仅在于是否存在激活的PIK3CA突变等位基因。在体内用NVP-BEZ235处理结肠肿瘤小鼠可导致PI3K的短暂抑制和mTORC1/mTORC2信号的持续阻断。光学结肠镜纵向肿瘤监测显示，对照组小鼠肿瘤大小增加97% (p = 0.01)，而治疗组小鼠肿瘤大小减少43% （p = 0.008）。体外分析显示，nvp - bez235治疗的肿瘤增殖减少56% (p = 0.003)，对细胞凋亡无影响，血管生成减少75% （p = 0.013）。这些研究为研究双PI3K/mTOR抑制剂NVP-BEZ235治疗PIK3CA野生型CRC的疗效提供了临床前基础。
To examine the in vitro and in vivo efficacy of the dual PI3K/mTOR inhibitor NVP-BEZ235 in treatment of PIK3CA wild-type colorectal cancer (CRC). PIK3CA mutant and wild-type human CRC cell lines were treated in vitro with NVP-BEZ235, and the resulting effects on proliferation, apoptosis, and signaling were assessed. Colonic tumors from a genetically engineered mouse (GEM) model for sporadic wild-type PIK3CA CRC were treated in vivo with NVP-BEZ235. The resulting effects on macroscopic tumor growth/regression, proliferation, apoptosis, angiogenesis, and signaling were examined. In vitro treatment of CRC cell lines with NVP-BEZ235 resulted in transient PI3K blockade, sustained decreases in mTORC1/mTORC2 signaling, and a corresponding decrease in cell viability (median IC50 = 9.0–14.3 nM). Similar effects were seen in paired isogenic CRC cell lines that differed only in the presence or absence of an activating PIK3CA mutant allele. In vivo treatment of colonic tumor-bearing mice with NVP-BEZ235 resulted in transient PI3K inhibition and sustained blockade of mTORC1/mTORC2 signaling. Longitudinal tumor surveillance by optical colonoscopy demonstrated a 97% increase in tumor size in control mice (p = 0.01) vs. a 43% decrease (p = 0.008) in treated mice. Ex vivo analysis of the NVP-BEZ235-treated tumors demonstrated a 56% decrease in proliferation (p = 0.003), no effects on apoptosis, and a 75% reduction in angiogenesis (p = 0.013). These studies provide the preclinical rationale for studies examining the efficacy of the dual PI3K/mTOR inhibitor NVP-BEZ235 in treatment of PIK3CA wild-type CRC.
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影响因子：
8.8
作者：
Cao, P.;Maira, S-M;Garcia-Echeverria, C.;Hedley, D. W.
通讯作者：
Hedley, D. W.
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：
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影响因子：
4.1
作者：
Currie, RA;Walker, KS;Lucocq, J
通讯作者：
Lucocq, J
影响因子：
5.7
作者：
Breuleux M;Klopfenstein M;Stephan C;Doughty CA;Barys L;Maira SM;Kwiatkowski D;Lane HA
通讯作者：
Lane HA
磷脂酰肌醇3-激酶过度激活导致拉帕替尼的抗性，这是由mTOR/磷脂酰/磷脂酰肌醇3-激酶抑制剂NVP-BEZ235逆转的。
影响因子：
11.2
作者：
Eichhorn PJ;Gili M;Scaltriti M;Serra V;Guzman M;Nijkamp W;Beijersbergen RL;Valero V;Seoane J;Bernards R;Baselga J
通讯作者：
Baselga J