Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Gut. 2021 Dec;70(12):2238-2248. doi: 10.1136/gutjnl-2020-321175. Epub 2021 Jan 24.
Gastro-oesophageal cancers (GEC) are resistant to therapy and lead to poor prognosis. The cancer stem cells (CSCs) and antiapoptotic pathways often confer therapy resistance. We sought to elucidate the antitumour action of a BCL-2 inhibitor, AT101 in GEC in vitro, in vivo and in a clinical trial.
Extensive preclinical studies in vitro and in vivo were carried out to establish the mechanism action of AT101 on targeting CSCs and antiapoptotic proteins. A pilot clinical trial in patients with GEC was completed with AT-101 added to standard chemoradiation.
Overexpression of BCL-2 and MCL-1 was noted in gastric cancer tissues (GC). AT-101 induced apoptosis, reduced proliferation and tumour sphere formation in MCL-1/BCL-2 high GC cells. Interestingly, AT101 dramatically downregulated genes () that control CSCs in GEC cell lines regardless of BCL-2/MCL-1 expression. Addition of docetaxel to AT-101 amplified its antiproliferation and induced apoptosis effects. In vivo studies confirmed the combination of AT101 and docetaxel demonstrated stronger antitumour activity accompanied with significant decrease of CSCs biomarkers (YAP1/SOX9). In a pilot clinical trial, 13 patients with oesophageal cancer (EC) received AT101 orally concurrently with chemoradiation. We observed dramatic clinical complete responses and encouraging overall survival in these patients. Clinical specimen analyses revealed that AT-101 dramatically reduced the expression of CSCs genes in treated EC specimens indicating antitumour activity of AT101 relies more on its anti-CSCs activity.
Our preclinical and clinical data suggest that AT-101 overcomes resistance by targeting CSCs pathways suggesting a novel mechanism of action of AT101 in patients with GEC.
胃食管癌症（GEC）对治疗有抵抗力，导致预后不良。癌症干细胞（CSCs）和抗凋亡途径常常赋予治疗耐药性。我们试图阐明 BCL-2 抑制剂 AT101 在体外、体内和临床试验中对 GEC 的抗肿瘤作用。
进行了广泛的体外和体内临床前研究，以确定 AT101 靶向 CSCs 和抗凋亡蛋白的作用机制。完成了一项针对 GEC 患者的 AT-101 联合标准放化疗的临床试验。
在胃癌组织（GC）中观察到 BCL-2 和 MCL-1 的过表达。AT-101 诱导 MCL-1/BCL-2 高 GC 细胞凋亡、减少增殖和肿瘤球体形成。有趣的是，AT101 显著下调了控制 GEC 细胞系中 CSCs 的基因（），而与 BCL-2/MCL-1 表达无关。将多西他赛添加到 AT-101 中增强了其抗增殖和诱导凋亡作用。体内研究证实，AT101 与多西他赛联合使用显示出更强的抗肿瘤活性，并伴有 CSCs 生物标志物（YAP1/SOX9）的显著减少。在一项临床试验中，13 名食管癌（EC）患者口服 AT101 同时接受放化疗。我们观察到这些患者出现了明显的临床完全缓解和令人鼓舞的总生存率。临床标本分析显示，AT-101 显著降低了治疗 EC 标本中 CSCs 基因的表达，表明 AT101 的抗肿瘤活性更多地依赖于其抗 CSCs 活性。
我们的临床前和临床数据表明，AT-101 通过靶向 CSCs 途径克服耐药性，提示 AT101 在 GEC 患者中的一种新的作用机制。
