Drug Development Program, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, 610 University Avenue, Toronto, Ontario, Canada.
BMC Med. 2012 Dec 11;10:161. doi: 10.1186/1741-7015-10-161.
The phosphatidylinositol 3-kinase (PI3K) pathway is commonly deregulated in cancer. In recent years, the results of the first phase I clinical trials with PI3K inhibitors have become available. In comparison to other targeted agents such v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitors in melanoma or crizotinib in anaplastic lymphoma receptor tyrosine kinase (ALK) translocated tumors, the number of objective responses to PI3K inhibitors is less dramatic. In this review we propose possible strategies to optimize the clinical development of PI3K inhibitors: by exploring the potential role of PI3K isoform-specific inhibitors in improving the therapeutic index, molecular characterization as a basis for patient selection, and the relevance of performing serial tumor biopsies to understand the associated mechanisms of drug resistance. The main focus of this review will be on PI3K isoform-specific inhibitors by describing the functions of different PI3K isoforms, the preclinical activity of selective PI3K isoform-specific inhibitors and the early clinical data of these compounds.
磷脂酰肌醇 3-激酶（PI3K）通路在癌症中通常失调。近年来，PI3K 抑制剂的首次 I 期临床试验结果已经公布。与其他靶向药物相比，如黑色素瘤中的 v-raf 鼠肉瘤病毒致癌基因同源物 B1（BRAF）抑制剂或间变性淋巴瘤受体酪氨酸激酶（ALK）易位肿瘤中的克唑替尼，PI3K 抑制剂的客观反应数量并不那么显著。在这篇综述中，我们提出了优化 PI3K 抑制剂临床开发的可能策略：通过探索 PI3K 同工型特异性抑制剂在提高治疗指数方面的潜在作用、作为患者选择基础的分子特征以及进行连续肿瘤活检的相关性，以了解相关的耐药机制。本综述的主要重点将是 PI3K 同工型特异性抑制剂，描述不同 PI3K 同工型的功能、选择性 PI3K 同工型特异性抑制剂的临床前活性以及这些化合物的早期临床数据。
