PKC-β as a therapeutic target in CLL: PKC inhibitor AEB071 demonstrates preclinical activity in CLL
PKC-β as a therapeutic target in CLL: PKC inhibitor AEB071 demonstrates preclinical activity in CLL
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DOI：
10.1182/blood-2014-05-574830
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发表时间：
2014-08-28
期刊：
影响因子：
20.3
通讯作者：
Byrd, John C.
中科院分区：
文献类型：
--
作者：
El-Gamal, Dalia;Williams, Katie;Byrd, John C.
针对慢性淋巴细胞白血病 (CLL) 的 B 细胞受体 (BCR) 信号传导已取得成功，并通过多种靶向治疗观察到持久缓解。蛋白激酶 C-β (PKC-β) 紧邻 BCR 下游，已被证明对 CLL 细胞体内存活和增殖至关重要。因此，我们在体外和体内评估了 sotrastaurin (AEB071)（一种口服有效的 PKC 抑制剂）对 CLL 细胞存活的影响。 AEB071 以剂量依赖性方式显示出针对 B-CLL 细胞的选择性细胞毒性。此外，AEB071 可减弱 BCR 介导的生存途径，抑制 CpG 诱导的 CLL 细胞体外生存和增殖，并有效阻断原代 CLL 细胞中微环境介导的生存信号传导途径。此外，AEB071 改变 β-连环蛋白表达，导致下游转录基因（如 c-Myc、Cyclin D1 和 CD44）减少。最后，我们的初步体内研究表明 AEB071 在 CLL 中具有有益的抗肿瘤特性。总而言之，我们的结果表明，靶向 PKC-β 有可能破坏微环境的信号传导，从而促进 CLL 细胞存活和潜在的耐药性。未来，有必要在复发性和难治性 CLL 患者的临床试验中，以 PKC 抑制剂 AEB071 作为单一疗法，以 PKC 为目标。
Targeting B-cell receptor (BCR) signaling in chronic lymphocytic leukemia (CLL) has been successful with durable remissions observed with several targeted therapeutics. Protein kinase C-beta (PKC-beta) is immediately downstream of BCR and has been shown to be essential to CLL cell survival and proliferation in vivo. We therefore evaluated sotrastaurin (AEB071), an orally administered potent PKC inhibitor, on CLL cell survival both in vitro and in vivo. AEB071 shows selective cytotoxicity against B-CLL cells in a dose-dependent manner. Additionally, AEB071 attenuates BCR-mediated survival pathways, inhibits CpG-induced survival and proliferation of CLL cells in vitro, and effectively blocks microenvironment-mediated survival signaling pathways in primary CLL cells. Furthermore, AEB071 alters beta-catenin expression, resulting in decreased downstream transcriptional genes as c-Myc, Cyclin D1, and CD44. Lastly, our preliminary in vivo studies indicate beneficial antitumor properties of AEB071 in CLL. Taken together, our results indicate that targeting PKC-beta has the potential to disrupt signaling from the microenvironment contributing to CLL cell survival and potentially drug resistance. Future efforts targeting PKC with the PKC inhibitor AEB071 as monotherapy in clinical trials of relapsed and refractory CLL patients are warranted.