Authors' Affiliations: Molecular Therapeutics Research Unit, Medical Oncology Department; and Experimental Therapeutics Group, Vall d'Hebron University Hospital, Barcelona, Spain.
Mol Cancer Ther. 2014 May;13(5):1021-31. doi: 10.1158/1535-7163.MCT-13-0639. Epub 2014 Apr 18.
The frequent activation of the PI3K/AKT/mTOR pathway in cancer, and its crucial role in cell growth and survival, has made it a much desired target for pharmacologic intervention. Following the regulatory approval of the rapamycin analogs everolimus and temsirolimus, recent years have seen an explosion in the number of phosphoinositide 3-kinase (PI3K) pathway inhibitors under clinical investigation. These include: ATP-competitive, dual inhibitors of class I PI3K and mTORC1/2; "pan-PI3K" inhibitors, which inhibit all four isoforms of class I PI3K (α, β, δ, γ); isoform-specific inhibitors of the various PI3K isoforms; allosteric and catalytic inhibitors of AKT; and ATP-competitive inhibitors of mTOR only (and thus mTORC1 and mTORC2). With so many agents in development, clinicians are currently faced with a wide array of clinical trials investigating a multitude of inhibitors with different mechanisms of action, being used both as single agents and in combination with other therapies. Here, we provide a review of the literature, with the aim of differentiating the genomic contexts in which these various types of inhibitors may potentially have superior activity.
PI3K/AKT/mTOR 通路在癌症中的频繁激活及其在细胞生长和存活中的关键作用，使其成为药物干预的理想靶点。在雷帕霉素类似物依维莫司和替西罗莫司获得监管批准后，近年来，在临床研究中，磷酸肌醇 3-激酶 (PI3K) 通路抑制剂的数量呈爆炸式增长。这些抑制剂包括：ATP 竞争性、I 类 PI3K 和 mTORC1/2 的双重抑制剂；“泛 PI3K”抑制剂，抑制 I 类 PI3K 的所有四种同工型（α、β、δ、γ）；各种 PI3K 同工型的同工型特异性抑制剂；AKT 的别构和催化抑制剂；以及仅针对 mTOR 的 ATP 竞争性抑制剂（因此针对 mTORC1 和 mTORC2）。由于有如此多的药物在开发中，临床医生目前面临着广泛的临床试验，研究了多种具有不同作用机制的抑制剂，这些抑制剂既作为单一药物使用，也与其他疗法联合使用。在这里，我们对文献进行了综述，旨在区分这些不同类型的抑制剂可能具有优势活性的基因组背景。
