Taselisib, a selective inhibitor of PIK3CA, is highly effective on PIK3CA-mutated and HER2/neu amplified uterine serous carcinoma in vitro and in vivo.
Taselisib, a selective inhibitor of PIK3CA, is highly effective on PIK3CA-mutated and HER2/neu amplified uterine serous carcinoma in vitro and in vivo.
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DOI：
10.1016/j.ygyno.2014.08.024
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发表时间：
2014-11
影响因子：
4.7
通讯作者：
Santin AD
中科院分区：
文献类型：
--
作者：
Lopez S;Schwab CL;Cocco E;Bellone S;Bonazzoli E;English DP;Schwartz PE;Rutherford T;Angioli R;Santin AD
评价PIK 3CA选择性抑制剂Taselisib对携带PIK 3CA突变和HER 2/neu基因扩增的原发性子宫浆液性癌（USC）的疗效。通过针对9种原代USC细胞系的流式细胞术活力测定体外评估对他塞利昔布的敏感性。通过测量细胞的DNA含量和通过流式细胞术测量S6蛋白的磷酸化来评估细胞周期分布和下游信号传导。还在小鼠模型中体内评价了他塞利昔布的临床前功效。四种USC细胞系通过FISH检测存在HER 2/neu基因扩增，其中两种细胞系存在致癌PIK 3CA突变。当与FISH阴性和PIK 3CA野生型的细胞系相比时，他塞利昔布在HER 2/neu FISH阳性和HER 2/neu FISH阳性/PIK 3CA突变的USC细胞系中引起强烈的差异性生长抑制（FISH+肿瘤中的他塞利昔布IC 50平均值±SEM= 0.042 ± 0.006 μ M对比FISH-肿瘤中的0.38 ± 0.06 μ M，P <0.0001）。他塞利昔布生长抑制与细胞周期G 0/G1期细胞百分比的显著和剂量依赖性增加以及S6磷酸化的剂量依赖性下降相关。在携带PIK 3CA突变和过表达HER 2/neu的USC小鼠异种移植物中，他塞利昔布在降低体内肿瘤生长方面具有高度活性（P=0.007）。与对照小鼠相比，用他塞利昔布治疗的小鼠具有显著更长的存活期（P<0.0001）。他塞利昔布代表了携带PIK 3CA突变和/或HER 2/neu基因扩增的患者的一种新的治疗选择。
To evaluate the efficacy of Taselisib, a selective inhibitor of PIK3CA, against primary uterine serous carcinomas (USC) harboring PIK3CA mutations and HER2/neu gene amplification. Sensitivity to taselisib was evaluated by flow-cytometry viability assays in vitro against nine primary USC cell lines. Cell cycle distribution and downstream signaling were assessed by measuring the DNA content of cells and by phosphorylation of the S6 protein by flow-cytometry. Preclinical efficacy of taselisib was also evaluated in vivo in a mouse model. Four USC cell lines harbored HER2/neu gene amplification by FISH and two of them harbored oncogenic PIK3CA mutations. Taselisib caused a strong differential growth inhibition in both HER2/neu FISH positive and HER2/neu FISH positive/PIK3CA mutated USC cell lines when compared to lines that were FISH negative and PIK3CA wild type (taselisib IC50 mean±SEM= 0.042 ± 0.006 µM in FISH+ versus 0.38 ± 0.06 µM in FISH- tumors, P <0.0001). Taselisib growth-inhibition was associated with a significant and dose-dependent increase in the percentage of cells in the G0/G1 phase of the cell cycle and dose-dependent decline in the phosphorylation of S6. Taselisib was highly active at reducing tumor growth in vivo in USC mouse xenografts harboring PIK3CA mutation and overexpressing HER2/neu (P=0.007). Mice treated with taselisib had significantly longer survival when compared to control mice (P<0.0001). Taselisib represents a novel therapeutic option in patients harboring PIK3CA mutations and/or HER2/neu gene amplification.
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影响因子：
4
作者：
English, Diana P.;Roque, Dana M.;Santin, Alessandro D.
通讯作者：
Santin, Alessandro D.
影响因子：
64.8
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影响因子：
5.6
作者：
HENDRICKSON, M;ROSS, J;KEMPSON, R
通讯作者：
KEMPSON, R
影响因子：
8.8
作者：
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影响因子：
30.8
作者：
Le Gallo, Matthieu;O'Hara, Andrea J.;Rudd, Meghan L.;Urick, Mary Ellen;Hansen, Nancy F.;O'Neil, Nigel J.;Price, Jessica C.;Zhang, Suiyuan;England, Bryant M.;Godwin, Andrew K.;Sgroi, Dennis C.;Hieter, Philip;Mullikin, James C.;Merino, Maria J.;Bell, Daphne W.
通讯作者：
Bell, Daphne W.