AKT Hyperactivation and the Potential of AKT-Targeted Therapy in Diffuse Large B-Cell Lymphoma
AKT Hyperactivation and the Potential of AKT-Targeted Therapy in Diffuse Large B-Cell Lymphoma
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DOI：
10.1016/j.ajpath.2017.04.009
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发表时间：
2017-08-01
影响因子：
6
通讯作者：
Young, Ken H.
中科院分区：
文献类型：
--
作者：
Wang, Jinfen;Xu-Monette, Zijun Y.;Young, Ken H.
AKT信号通路对肿瘤细胞的增殖和存活具有重要意义。AKT活化在弥漫性大b细胞淋巴瘤（DLBCL）中的临床意义尚未得到很好的分析。在这里，我们评估了522名DLBCL患者中磷酸化AKT （p-AKT）的表达。我们发现，在24.3%的研究队列中观察到高水平的p-AKT核表达与显著较差的无进展生存和Myc和Bcl-2过表达相关。然而，多变量分析表明AKT过度激活不是一个独立的因素。miRNA谱分析显示，63个与磷脂酰肌醇3-激酶/AKT/雷帕霉素通路机制靶点直接或间接相关的miRNA在p-AKT高核表达和低核表达的dlbcl中存在差异表达。我们进一步在26个具有代表性的DLBCL细胞系中使用高选择性AKT抑制剂MK-2206靶向AKT信号传导，并使用逆相蛋白阵列描绘信号传导变化。MK-2206治疗抑制淋巴瘤细胞活力，MK-2206敏感性与DLBCL细胞中AKT激活状态相关。在MK-2206处理下，p-AKT水平和AKT信号的下游目标显著降低，可能是由于反馈抑制减少；蛋白激酶和磷脂酰肌醇3-激酶的表达及其他代偿途径也被诱导。本研究证实了AKT在DLBCL中过度激活的临床和治疗意义，并提示AKT抑制剂需要与其他靶向药物联合治疗DLBCL以获得最佳临床疗效。
AKT signaling is important for proliferation and survival of tumor cells. The clinical significance of AKT activation in diffuse large B-cell lymphoma (DLBCL) is not well analyzed. Here, we assessed expression of phosphorylated AKT (p-AKT) in 522 DLBCL patients. We found that high levels of p-AKT nuclear expression, observed in 24.3% of the study cohort, were associated with significantly worse progression free survival and Myc and Bcl-2 overexpression. However, multivariate analysis indicated that AKT hyperactivation was not an independent factor. miRNA profiling analysis demonstrated that 63 miRNAs directly or indirectly related to the phosphatidylinositol 3-kinase/AKT/mechanistic target of rapamycin pathway were differentially expressed between DLBCLs with high and low p-AKT nuclear expression. We further targeted AKT signaling using a highly selective AKT inhibitor MK-2206 in 26 representative DLBCL cell lines and delineated signaling alterations using a reverse-phase protein array. MK-2206 treatment inhibited lymphoma cell viability, and MK-2206 sensitivity correlated with AKT activation status in DLBCL cells. On MK-2206 treatment, p-AKT Levels and downstream targets of AKT signaling were significantly decreased, likely because of the decreased feedback repression; Rictor and phosphatidylinositol 3-kinase expression and other compensatory pathways were also induced. This study demonstrates the clinical and therapeutic implications of AKT hyperactivation in DLBCL and suggests that AKT inhibitors need to be combined with other targeted agents for DLBCL to achieve optimal clinical efficacy.