ONC201 Demonstrates Antitumor Effects in Both Triple-Negative and Non-Triple-Negative Breast Cancers through TRAIL-Dependent and TRAIL-Independent Mechanisms.
ONC201 Demonstrates Antitumor Effects in Both Triple-Negative and Non-Triple-Negative Breast Cancers through TRAIL-Dependent and TRAIL-Independent Mechanisms.
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ONC201 通过 TRAIL 依赖性和 TRAIL 独立机制在三阴性和非三阴性乳腺癌中显示出抗肿瘤作用。
DOI：
10.1158/1535-7163.mct-17-0121
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发表时间：
2017-07
影响因子：
5.7
通讯作者：
El-Deiry WS
中科院分区：
文献类型：
--
作者：
Ralff MD;Kline CLB;Küçükkase OC;Wagner J;Lim B;Dicker DT;Prabhu VV;Oster W;El-Deiry WS
乳腺癌是癌症相关死亡的主要原因。TRAIL作为一种癌症治疗方法已引起人们的兴趣，但只有三阴性乳腺癌(TNBC)的一部分对TRAIL敏感。小分子ONC201可诱导TRAIL及其受体DR5的表达。ONC201已进入晚期癌症的临床试验。在这里，我们显示ONC201对TNBC和非TNBC细胞(n=13)都有效。部分TNBC和非TNBC细胞屈服于ONC201诱导的细胞死亡。在2/8的TNBC细胞系中，ONC201处理诱导caspase-8裂解和细胞死亡，并被TRAIL中和抗体RIK2阻断。在MDA-MB-468异种移植模型中，ONC201的促凋亡作用转化为体内疗效。在大多数被测试的TNBC细胞系中(6/8)，ONC201具有抗增殖作用，但不诱导细胞凋亡。ONC201降低细胞周期蛋白D1的表达，导致细胞聚集在细胞周期的G1期。PRb的表达与对ONC201抗增殖作用的敏感性有关，该化合物与不太敏感的细胞中的紫杉烷具有协同作用。所有非TNBC细胞(n=5)在ONC201处理后都受到生长抑制，与TRAIL不同的是，有一组(n=2)细胞显示PARP切割。在这些细胞中，ONC201诱导的细胞死亡不依赖于TRAIL。我们的数据表明，ONC201通过TRAIL依赖和TRAIL非依赖机制，在广泛的乳腺癌亚型中具有强大的抗增殖和促凋亡作用。这些发现为开发ONC201作为一种单一药物和/或与已批准的乳腺癌治疗方法相结合提供了临床前的理论基础。
Breast cancer is a major cause of cancer-related death. TRAIL has been of interest as a cancer therapeutic, but only a subset of triple negative breast cancers (TNBC) is sensitive to TRAIL. The small molecule ONC201 induces expression of TRAIL and its receptor DR5. ONC201 has entered clinical trials in advanced cancers. Here we show that ONC201 is efficacious against both TNBC and non-TNBC cells (n=13). A subset of TNBC and non-TNBC cells succumb to ONC201-induced cell death. In 2/8 TNBC cell lines, ONC201 treatment induces caspase-8 cleavage and cell death that is blocked by TRAIL-neutralizing antibody RIK2. The pro-apoptotic effect of ONC201 translates to in vivo efficacy in the MDA-MB-468 xenograft model. In most TNBC lines tested (6/8) ONC201 has an anti-proliferative effect but does not induce apoptosis. ONC201 decreases cyclin D1 expression and causes an accumulation of cells in the G1 phase of the cell cycle. pRb expression is associated with sensitivity to the anti-proliferative effects of ONC201, and the compound synergizes with taxanes in less sensitive cells. All non-TNBC cells (n=5) are growth inhibited following ONC201 treatment, and unlike what has been observed with TRAIL, a subset (n=2) show PARP cleavage. In these cells, cell death induced by ONC201 is TRAIL-independent. Our data demonstrate that ONC201 has potent anti-proliferative and pro-apoptotic effects in a broad range of breast cancer subtypes, through TRAIL-dependent and TRAIL-independent mechanisms. These findings develop a pre-clinical rationale for developing ONC201 as a single agent and/or in combination with approved therapies in breast cancer.