A chemical screen in diverse breast cancer cell lines reveals genetic enhancers and suppressors of sensitivity to PI3K isoform-selective inhibition.
A chemical screen in diverse breast cancer cell lines reveals genetic enhancers and suppressors of sensitivity to PI3K isoform-selective inhibition.
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DOI：
10.1042/bj20080639
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发表时间：
2008-10-01
期刊：
影响因子：
--
通讯作者：
Stokoe D
中科院分区：
文献类型：
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作者：
Torbett NE;Luna-Moran A;Knight ZA;Houk A;Moasser M;Weiss W;Shokat KM;Stokoe D
磷脂酰肌醇-3-激酶（PI 3 K）途径调节细胞增殖、存活和迁移，因此对于靶向癌症治疗非常感兴趣。在一组不同的乳腺癌细胞系中使用一组小分子PI 3 K亚型选择性抑制剂，我们证明了生物化学和生物学反应是高度可变的，并依赖于存在的遗传改变。p110α抑制剂在大多数检测的细胞系中通常可有效抑制Akt和S6的磷酸化，这两种磷酸化是PI 3 K信号传导的两个下游组分。相比之下，110β选择性抑制剂仅减少PTEN突变细胞系中的Akt磷酸化，并且与S6磷酸化的较少减少相关。PI 3 K抑制剂通过在细胞周期的G1期引起细胞周期停滞来降低细胞活力，其中多靶向抑制剂引起最有效的作用。表达突变型Ras的细胞对PI 3 K抑制的细胞周期效应具有抗性，这可以使用Ras信号通路的抑制剂逆转。总之，我们的数据表明，这些化合物，单独或在适当的组合，可能是有用的乳腺癌治疗，当在适当的遗传背景下使用。
The Phosphoinositide-3-kinase (PI3K) pathway regulates cell proliferation, survival and migration and is consequently of great interest for targeted cancer therapy. Using a panel of small molecule PI3K isoform-selective inhibitors in a diverse set of breast cancer cell lines, we demonstrate that the biochemical and biological responses were highly variable and dependent on the genetic alterations present. p110α inhibitors were generally effective in inhibiting the phosphorylation of Akt and S6, two downstream components of PI3K signaling, in most cell lines examined. In contrast, 110β selective inhibitors only reduced Akt phosphorylation in PTEN mutant cell lines, and was associated with a lesser decrease in S6 phosphorylation. PI3K inhibitors reduced cell viability by causing a cell cycle arrest in the G1 phase of the cell cycle, with multi-targeted inhibitors causing the most potent effects. Cells expressing mutant Ras were resistant to the cell cycle effects of PI3K inhibition, which could be reversed using inhibitors of Ras signaling pathways. Taken together our data indicates that these compounds, alone or in suitable combinations, may be useful as breast cancer therapeutics, when used in appropriate genetic contexts.