文章：

靶向PI3K信号在癌症中的作用：机遇、挑战和局限

Targeting PI3K signalling in cancer: opportunities, challenges and limitations

原文发布日期：2009-08-01

DOI: 10.1038/nrc2664

类型: Review Article

开放获取: 否

要点：

1. There are several therapeutics that target the PI3K–Akt pathway in clinical development for the treatment of cancer. These include dual PI3K–mTOR inhibitors, PI3K inhibitors, Akt inhibitors and mTOR complex catalytic site inhibitors.
2. The PI3K–Akt pathway is inappropriately activated in many cancers. The pathway is activated by receptor tyrosine kinases, as well as by the genetic mutation and amplification of key pathway components.
3. The most effective type of therapeutic used to inhibit this pathway is likely to depend on the particular mechanism of PI3K–Akt activation in a cancer.
4. So far, preclinical data suggest that PI3K–Akt pathway inhibitors might have single-agent activity in breast cancers with ERBB2 amplifications or PIK3CA mutations. These drugs might also be effective in overcoming acquired resistance to therapies that target receptor tyrosine kinases (such as acquired resistance to trastuzumab or erlotinib).
5. Drugs targeting the PI3K–Akt pathway might most effectively treat cancers when they are used in combination with other targeted therapies, such as MEK inhibitors.
6. Effective clinical development will centre on determining why these compounds fail when they do. It will be important to determine whether a drug could not effectively downregulate PI3K–Akt signalling or if effective inhibition of the pathway was not sufficient to produce a clinical response.

要点翻译：

1. 目前有数种针对PI3K–Akt通路的治疗药物正处于癌症治疗的临床研发阶段，包括双重PI3K–mTOR抑制剂、PI3K抑制剂、Akt抑制剂以及mTOR复合物催化位点抑制剂。
2. PI3K–Akt通路在多种癌症中异常激活。该通路可被受体酪氨酸激酶以及关键通路组分的基因突变和扩增所激活。
3. 抑制该通路最有效的治疗药物类型，很可能取决于癌症中PI3K–Akt激活的具体机制。
4. 截至目前，临床前数据表明PI3K–Akt通路抑制剂可能在携带ERBB2扩增或PIK3CA突变的乳腺癌中具有单药活性。这些药物或能有效克服针对受体酪氨酸激酶疗法（如曲妥珠单抗或厄洛替尼）的获得性耐药。
5. 当与其他靶向药物（如MEK抑制剂）联合使用时，靶向PI3K–Akt通路的药物可能会更有效地治疗癌症。
6. 有效的临床研发重点在于明确这些化合物治疗失败的原因。关键需要确定是药物无法有效下调PI3K–Akt信号传导，还是即便有效抑制该通路仍不足以产生临床反应。

英文摘要：

There are ample genetic and laboratory studies that suggest the PI3K–Akt pathway is vital to the growth and survival of cancer cells. Inhibitors targeting this pathway are entering the clinic at a rapid pace. In this Review, the therapeutic potential of drugs targeting PI3K–Akt signalling for the treatment of cancer is discussed. I focus on the advantages and drawbacks of different treatment strategies for targeting this pathway, the cancers that might respond best to these therapies and the challenges and limitations that confront their clinical development.

摘要翻译： 

大量遗传学和实验室研究表明，PI3K–Akt通路对癌细胞的生长和存活至关重要。针对该通路的抑制剂正迅速进入临床。本文综述了靶向PI3K–Akt信号通路药物治疗癌症的治疗潜力。我重点探讨了不同靶向策略的优势与不足、可能最获益的癌种，以及其临床开发所面临的挑战与局限。

原文链接：

Targeting PI3K signalling in cancer: opportunities, challenges and limitations