AZD2014, an Inhibitor of mTORC1 and mTORC2, Is Highly Effective in ER+ Breast Cancer When Administered Using Intermittent or Continuous Schedules
AZD2014, an Inhibitor of mTORC1 and mTORC2, Is Highly Effective in ER+ Breast Cancer When Administered Using Intermittent or Continuous Schedules
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DOI：
10.1158/1535-7163.mct-15-0365
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发表时间：
2015-11-01
影响因子：
5.7
通讯作者：
Cosulich, Sabina C.
中科院分区：
文献类型：
--
作者：
Guichard, Sylvie M.;Curwen, Jon;Cosulich, Sabina C.
mTOR是一种非典型的丝氨酸苏氨酸激酶，参与调节主要的细胞功能，如营养物质感应、生长和增殖。mTOR是多蛋白复合物mTORC1和mTORC2的一部分，其已被证明在细胞过程的调节中发挥关键但功能不同的作用。目前的临床mTOR抑制剂仅抑制mTORC 1复合物，并且是大环内酯雷帕霉素的衍生物（雷帕霉素类似物）。在雌激素受体阳性（ER+）乳腺癌患者中观察到雷帕霉素类似物与内分泌治疗（如芳香酶抑制剂）联合使用的鼓舞人心的效果。AZD 2014是一种mTOR的小分子ATP竞争性抑制剂，可抑制mTORC 1和mTORC 2复合物，对mTORC 1的抑制作用大于临床批准的雷帕霉素类似物。在这里，我们证明了AZD 2014在多种细胞系中具有广泛的抗增殖作用，包括对激素治疗具有获得性耐药性的ER+乳腺模型和对雷帕霉素类似物具有获得性耐药性的细胞系。在体内，AZD2014在几种异种移植和原代外植体模型中诱导剂量依赖性肿瘤生长抑制。AZD 2014的抗肿瘤活性与mTORC 1和mTORC 2底物的调节相关，与其作用机制一致。与氟维司群联合使用时，AZD 2014在连续给药或使用间歇给药方案时诱导肿瘤消退。AZD 2014间歇给药的能力，以及其阻断mTORC 1和mTORC 2复合物信号传导的能力，使该化合物成为临床上与内分泌疗法联合使用的理想候选药物。AZD 2014目前处于II期临床试验阶段。(C)2015年AACR。
mTOR is an atypical serine threonine kinase involved in regulating major cellular functions, such as nutrients sensing, growth, and proliferation. mTOR is part of the multiprotein complexes mTORC1 and mTORC2, which have been shown to play critical yet functionally distinct roles in the regulation of cellular processes. Current clinical mTOR inhibitors only inhibit the mTORC1 complex and are derivatives of the macrolide rapamycin (rapalogs). Encouraging effects have been observed with rapalogs in estrogen receptor-positive (ER+) breast cancer patients in combination with endocrine therapy, such as aromatase inhibitors. AZD2014 is a small-molecule ATP competitive inhibitor of mTOR that inhibits both mTORC1 and mTORC2 complexes and has a greater inhibitory function against mTORC1 than the clinically approved rapalogs. Here, we demonstrate that AZD2014 has broad antipro-liferative effects across multiple cell lines, including ER+ breast models with acquired resistance to hormonal therapy and cell lines with acquired resistance to rapalogs. In vivo, AZD2014 induces dose-dependent tumor growth inhibition in several xenograft and primary explant models. The antitumor activity of AZD2014 is associated with modulation of both mTORC1 and mTORC2 substrates, consistent with its mechanism of action. In combination with fulvestrant, AZD2014 induces tumor regressions when dosed continuously or using intermittent dosing schedules. The ability to dose AZD2014 intermittently, together with its ability to block signaling from both mTORC1 and mTORC2 complexes, makes this compound an ideal candidate for combining with endocrine therapies in the clinic. AZD2014 is currently in phase II clinical trials. (C) 2015 AACR.