Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib.
Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib.
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在依维莫司和pazopanib的I期试验中激活患者的MTOR突变。
DOI：
10.1158/2159-8290.cd-13-0353
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发表时间：
2014-05
期刊：
影响因子：
28.2
通讯作者：
Rosenberg JE
中科院分区：
文献类型：
--
作者：
Wagle N;Grabiner BC;Van Allen EM;Hodis E;Jacobus S;Supko JG;Stewart M;Choueiri TK;Gandhi L;Cleary JM;Elfiky AA;Taplin ME;Stack EC;Signoretti S;Loda M;Shapiro GI;Sabatini DM;Lander ES;Gabriel SB;Kantoff PW;Garraway LA;Rosenberg JE
了解靶向抗癌疗法敏感性的遗传机制可能会改善患者选择、治疗反应和合理的治疗设计。增进这种理解的一种方法是对特殊反应者进行详细研究：对治疗具有意想不到的敏锐敏感性或持久反应的罕见患者。我们在帕唑帕尼和依维莫司治疗晚期实体瘤的 I 期研究中发现了一位特殊的反应者。对本次试验中获得 14 个月完全缓解的患者进行的全外显子组测序显示，依维莫司的靶标 mTOR 存在两个同时突变。体外实验表明，这两种突变都在激活，这表明该患者对依维莫司高度敏感的生物学机制。使用精准（或“个性化”）医学方法来筛查癌症患者 mTOR 通路的改变可能有助于识别可能受益于 mTOR 靶向治疗的患者亚群。
Understanding the genetic mechanisms of sensitivity to targeted anticancer therapies may improve patient selection, response to therapy, and rational treatment designs. One approach to increase this understanding involves detailed studies of exceptional responders: rare patients with unexpected exquisite sensitivity or durable responses to therapy. We identified an exceptional responder in a phase I study of pazopanib and everolimus in advanced solid tumors. Whole exome sequencing of a patient with a 14-month complete response on this trial revealed two simultaneous mutations in mTOR, the target of everolimus. In vitro experiments demonstrate that both mutations are activating, suggesting a biological mechanism for exquisite sensitivity to everolimus in this patient. The use of precision (or “personalized”) medicine approaches to screen cancer patients for alterations in the mTOR pathway may help to identify subsets of patients who may benefit from targeted therapies directed against mTOR.