文章：

PI3K在癌症中的不同作用：亚型、激活模式和治疗靶向

PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting

原文发布日期：2014-12-23

DOI: 10.1038/nrc3860

类型: Review Article

开放获取: 否

要点：

1. Oncogenic mutation of the phosphatidylinositol 3-kinase (PI3K) catalytic isoform p110α is frequent in human cancers, whereas the catalytic isoforms p110β, p110δ and p110γ are rarely mutated but can be overexpressed. Mutation or loss of expression of regulatory isoform p85α is also associated with cancer.
2. Although class IA PI3K catalytic isoforms share structural and substrate similarities, they have specific roles in mediating PI3K signalling in different physiological and oncogenic contexts.
3. Cancer cells with upregulation or mutation of receptor tyrosine kinases (RTKs), oncogenic RAS mutations or activating p110α mutations are highly dependent on p110α, even in the presence of mutation or loss of PTEN.
4. In many cases, tumorigenesis that is driven by PTEN loss depends on p110β. However, PI3K isoform dependence in PTEN-deficient transformation may be governed by other PI3K isoforms that are dominant in a tissue or compartment, or shifted by coexisting oncogenic mutations.
5. Isoforms p110α, p110δ and p110γ bind to and are activated by RAS subfamily GTPases, while p110β binds to and is activated by RHO subfamily GTPases RAC1 and CDC42.
6. Non-isoform-selective pan-PI3K inhibitors have not yielded exciting clinical results, but second-generation PI3K drugs that target individual PI3K isoforms may be able to achieve greater therapeutic efficacy by offering improved specificity and reduced toxicity.
7. The p110δ-selective inhibitor idelalisib has been remarkably effective in clinical trials for patients with B cell malignancies, while p110α-selective inhibitors have shown promise in early-phase trials for patients with solid tumours with PIK3CA mutations or HER2 amplification.
8. Intrinsic and acquired resistance mechanisms are a continuing challenge for PI3K-directed therapeutic approaches. To overcome this, combination therapies and alternative dosing strategies are being developed and evaluated in both preclinical and clinical settings.

要点翻译：

1. 磷脂酰肌醇3-激酶（PI3K）催化亚基p110α的致癌突变在人类癌症中较为常见，而催化亚基p110β、p110δ和p110γ虽罕见突变但可能过表达。调节亚基p85α的突变或表达缺失也与癌症相关。
2. 尽管IA类PI3K催化亚基具有相似的结构和底物特性，但在不同生理及致癌背景下，它们介导PI3K信号传导的功能存在特异性。
3. 受体酪氨酸激酶（RTK）上调或突变、RAS致癌突变或p110α激活突变导致的癌细胞高度依赖p110α，即便存在PTEN突变或缺失。
4. 在许多情况下，由PTEN缺失驱动的肿瘤发生依赖于p110β。然而，PTEN缺陷型转化中的PI3K亚基依赖性可能受组织或细胞区室中占主导地位的其他PI3K亚基调控，或受共存致癌突变影响而发生转移。
5. p110α、p110δ和p110γ亚基与RAS亚家族GTP酶结合并被激活，而p110β则与RHO亚家族GTP酶RAC1和CDC42结合并被激活。
6. 非亚型选择性泛PI3K抑制剂尚未取得令人振奋的临床结果，但针对特定PI3K亚基的第二代PI3K药物通过提升特异性、降低毒性，可能获得更佳疗效。
7. p110δ选择性抑制剂艾代拉里斯在B细胞恶性肿瘤临床试验中疗效显著，而p110α选择性抑制剂在携带PIK3CA突变或HER2扩增的实体瘤早期试验中展现出潜力。
8. 内在性与获得性耐药机制始终是PI3K靶向治疗的挑战。为克服这一难题，临床前及临床研究正在积极开发并评估联合疗法与替代给药策略。。

英文摘要：

Phosphatidylinositol 3-kinases (PI3Ks) are crucial coordinators of intracellular signalling in response to extracellular stimuli. Hyperactivation of PI3K signalling cascades is one of the most common events in human cancers. In this Review, we discuss recent advances in our knowledge of the roles of specific PI3K isoforms in normal and oncogenic signalling, the different ways in which PI3K can be upregulated, and the current state and future potential of targeting this pathway in the clinic.

摘要翻译： 

磷脂酰肌醇3-激酶（PI3Ks）是响应胞外刺激时协调胞内信号传导的关键分子。PI3K信号级联的过度激活是人类癌症中最常见的事件之一。在本综述中，我们讨论了对特定PI3K亚型在正常及致癌信号中作用的最新认识、PI3K可被上调的不同机制，以及目前针对该通路的临床干预现状与未来潜力。

原文链接：

PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting