Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Clin Cancer Res. 2018 Aug 15;24(16):3967-3980. doi: 10.1158/1078-0432.CCR-17-3004. Epub 2018 Apr 17.
B-cell lymphoma-2 (BCL-2), an antiapoptotic protein often dysregulated in B-cell lymphomas, promotes cell survival and provides protection from stress. A recent phase I first-in-human study of the BCL-2 inhibitor venetoclax in non-Hodgkin lymphoma showed an overall response rate of 44%. These promising clinical results prompted our examination of the biological effects and mechanism of action underlying venetoclax activity in aggressive B-cell lymphoma, including mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL). MCL and DLBCL cell lines, primary patient samples, and patient-derived xenograft (PDX) models were utilized to examine venetoclax efficacy. Furthermore, the mechanisms underlying venetoclax response and the development of venetoclax resistance were evaluated using proteomics analysis and Western blotting. Potential biomarkers linked to venetoclax activity and targeted combination therapies that can augment venetoclax response were identified. We demonstrate that DLBCL and MCL cell lines, primary patient samples, and PDX mouse models expressing high BCL-2 levels are extremely sensitive to venetoclax treatment. Proteomics studies showed that venetoclax substantially alters the expression levels and phosphorylation status of key proteins involved in cellular processes, including the DNA damage response, cell metabolism, cell growth/survival, and apoptosis. Short- and long-term exposure to venetoclax inhibited PTEN expression, leading to enhanced AKT pathway activation and concomitant susceptibility to PI3K/AKT inhibition. Intrinsic venetoclax-resistant cells possess high AKT activation and are highly sensitive to PI3K/AKT inhibition. These findings demonstrate the on-target effect of venetoclax and offer potential mechanisms to overcome acquired and intrinsic venetoclax resistance through PI3K/AKT inhibition. .
B 细胞淋巴瘤-2（BCL-2）是一种抗凋亡蛋白，在 B 细胞淋巴瘤中经常失调，它促进细胞存活并提供应激保护。最近一项关于 BCL-2 抑制剂 Venetoclax 在非霍奇金淋巴瘤中的 I 期首次人体研究显示，总体反应率为 44%。这些有希望的临床结果促使我们研究 Venetoclax 在侵袭性 B 细胞淋巴瘤（包括套细胞淋巴瘤[MCL]和弥漫性大 B 细胞淋巴瘤[DLBCL]）中的生物学效应和作用机制。我们利用 MCL 和 DLBCL 细胞系、原发患者样本和患者衍生的异种移植（PDX）模型来研究 Venetoclax 的疗效。此外，我们还通过蛋白质组学分析和 Western blot 评估了 Venetoclax 反应的机制以及 Venetoclax 耐药的发展。确定了与 Venetoclax 活性相关的潜在生物标志物和可以增强 Venetoclax 反应的靶向联合治疗方法。我们证明，表达高 BCL-2 水平的 DLBCL 和 MCL 细胞系、原发患者样本和 PDX 小鼠模型对 Venetoclax 治疗非常敏感。蛋白质组学研究表明，Venetoclax 极大地改变了细胞过程中关键蛋白的表达水平和磷酸化状态，包括 DNA 损伤反应、细胞代谢、细胞生长/存活和细胞凋亡。短期和长期暴露于 Venetoclax 抑制了 PTEN 的表达，导致 AKT 通路的激活增强，并伴随对 PI3K/AKT 抑制的敏感性。内在 Venetoclax 耐药细胞具有高 AKT 激活，对 PI3K/AKT 抑制高度敏感。这些发现证明了 Venetoclax 的靶标效应，并提供了通过 PI3K/AKT 抑制克服获得性和内在 Venetoclax 耐药性的潜在机制。
