Isoform-Specific Phosphoinositide 3-Kinase Inhibitors Exert Distinct Effects in Solid Tumors
Isoform-Specific Phosphoinositide 3-Kinase Inhibitors Exert Distinct Effects in Solid Tumors
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DOI：
10.1158/0008-5472.can-09-2525
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发表时间：
2010-02-01
期刊：
影响因子：
11.2
通讯作者：
Belvin, Marcia
中科院分区：
文献类型：
--
作者：
Edgar, Kyle A.;Wallin, Jeffrey J.;Belvin, Marcia
正在开发针对磷酸肌醇3-激酶（PI 3 K）途径的治疗性抑制剂，该途径的失调驱动许多癌症中的肿瘤生长和存活。在哺乳动物中有八种PI 3 K，分为三类。IA类PI 3 K（p110 α、p110 β和p110 δ）对细胞生长和存活至关重要，其中p110 a亚型在癌中是最重要的。在这项研究中，我们检查了IA类PI 3 Ks的小分子抑制剂的作用，以探索癌细胞中不同亚型的贡献。在细胞活力测定中，在用p110 α/δ或p110 α/β/δ抑制剂处理的具有野生型或活化突变型PI 3 K基因的癌细胞中观察到类似的反应。相比之下，PTEN阴性细胞系倾向于对p110 α/β抑制剂的反应性较低（总体为4倍）。将p110 α/δ抑制剂与p110 β抑制剂组合导致与p110 α/β/δ抑制剂相当的效力。在体内证实了疗效的差异。药效学生物标志物分析显示，对p110 β亚型效力不足的抑制剂在抑制PTEN阴性肿瘤异种移植物中的PI 3 K途径方面效果较差。我们的研究结果表明，PTEN阴性肿瘤患者可能优先受益于I类PI 3 K抑制剂，能够抑制p110 β亚型的治疗。Cancer Res; 70（3）; 1164-72. (C)2010年AACR。
Therapeutic inhibitors are being developed against the phosphoinositide 3-kinase (PI3K) pathway, the deregulation of which drives tumor growth and survival in many cancers. There are eight PI3Ks in mammals divided into three classes. Class IA PI3Ks (p110 alpha, p110 beta, and p110 delta) are critical for cell growth and survival, with the p110a isoform implicated as the most important in carcinomas. In this study, we examined the effects of small-molecule inhibitors of class IA PI3Ks to explore the contributions of different isoforms in cancer cells. Similar responses were seen in cancer cells with wild- type or activated mutant PI3K genes treated with p110 alpha/delta or p110 alpha/beta/delta inhibitors in cell viability assays. In contrast, PTEN-negative cell lines tended to be less responsive (4-fold overall) to an inhibitor of p110 alpha/beta versus p110 alpha/beta/delta. Combining a p110 alpha/delta inhibitor with a p110 beta inhibitor resulted in comparable potency to the p110 alpha/beta/delta inhibitor. The disparity in efficacy was confirmed in vivo. Pharmacodynamic biomarker analysis revealed that an inhibitor with insufficient potency against the p110 beta isoform was less effective at inhibiting the PI3K pathway in PTEN-negative tumor xenografts. Our results imply that patients with PTEN-negative tumors may preferentially benefit from treatment with a class I PI3K inhibitor that is capable of inhibiting the p110 beta isoform. Cancer Res; 70(3); 1164-72. (C) 2010 AACR.