A drug targeting only p110α can block phosphoinositide 3-kinase signalling and tumour growth in certain cell types.
A drug targeting only p110α can block phosphoinositide 3-kinase signalling and tumour growth in certain cell types.
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DOI：
10.1042/bj20110502
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发表时间：
2011-08-15
期刊：
影响因子：
--
通讯作者：
Shepherd PR
中科院分区：
文献类型：
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作者：
Jamieson S;Flanagan JU;Kolekar S;Buchanan C;Kendall JD;Lee WJ;Rewcastle GW;Denny WA;Singh R;Dickson J;Baguley BC;Shepherd PR
PI 3 K（磷酸肌醇3-激酶）信号传导的遗传改变在癌症中很常见，包括PTEN（10号染色体上缺失的磷酸酶和张力蛋白同源物）的缺失、PIK 3CA的扩增和PIK 3CA基因两个不同区域的突变。这表明靶向PI 3 K，特别是p110α的药物可能对治疗癌症有用。广谱抑制PI 3 K可有效防止生长因子信号传导和肿瘤生长，但尚未获得合适的p110α抑制剂来研究单独抑制该亚型的作用。在本研究中，我们表征了一种新的小分子A66，表明S-对映体是一种高度特异性和选择性的p110α抑制剂。使用分子建模和生物化学研究，我们解释了这种选择性的基础。使用一组亚型选择性抑制剂，我们发现在所有测试的细胞系中，抑制p110α/p110β/p110δ的累加效应减弱了胰岛素向Akt/PKB（蛋白激酶B）的信号传导。然而，在某些细胞系中，单独抑制p110α足以阻断胰岛素向Akt/PKB的信号传导。应答细胞系均在PIK 3CA中携带H1047 R突变，并具有高水平的p110α和Ia类PI 3 K活性。这可能解释了这些细胞对p110α抑制剂的敏感性增加。我们评估了Akt/PKB的激活和异种移植模型中的肿瘤生长，发现来自两个应答细胞系的肿瘤也对体内A66有应答。这些结果表明，单独抑制p110α有可能阻断生长因子信号传导并减少肿瘤亚组的生长。
Genetic alterations in PI3K (phosphoinositide 3-kinase) signalling are common in cancer and include deletions in PTEN (phosphatase and tensin homologue deleted on chromosome 10), amplifications of PIK3CA and mutations in two distinct regions of the PIK3CA gene. This suggests drugs targeting PI3K, and p110α in particular, might be useful in treating cancers. Broad-spectrum inhibition of PI3K is effective in preventing growth factor signalling and tumour growth, but suitable inhibitors of p110α have not been available to study the effects of inhibiting this isoform alone. In the present study we characterize a novel small molecule, A66, showing the S-enantiomer to be a highly specific and selective p110α inhibitor. Using molecular modelling and biochemical studies, we explain the basis of this selectivity. Using a panel of isoform-selective inhibitors, we show that insulin signalling to Akt/PKB (protein kinase B) is attenuated by the additive effects of inhibiting p110α/p110β/p110δ in all cell lines tested. However, inhibition of p110α alone was sufficient to block insulin signalling to Akt/PKB in certain cell lines. The responsive cell lines all harboured H1047R mutations in PIK3CA and have high levels of p110α and class-Ia PI3K activity. This may explain the increased sensitivity of these cells to p110α inhibitors. We assessed the activation of Akt/PKB and tumour growth in xenograft models and found that tumours derived from two of the responsive cell lines were also responsive to A66 in vivo. These results show that inhibition of p110α alone has the potential to block growth factor signalling and reduce growth in a subset of tumours.