Kim Joo Hyun, Kim Won Seog, Ryu Kyungju, Kim Seok Jin, Park Chaehwa
a Research Institute for Future Medicine, Samsung Medical Center , Sungkyunkwan University School of Medicine , Seoul , Korea ;
b Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center , Sungkyunkwan University School of Medicine , Seoul , Korea.
Leuk Lymphoma. 2016;57(6):1413-22. doi: 10.3109/10428194.2015.1113276. Epub 2015 Dec 24.
Blockage of B cell receptor signaling with ibrutinib presents a promising clinical approach for treatment of B-cell malignancies. However, many patients show primary resistance to the drug or develop secondary resistance. In the current study, cDNA microarray and Western blot analyses revealed CD79B upregulation in the activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL) that display differential resistance to ibrutinib. CD79B overexpression was sufficient to induce resistance to ibrutinib and enhanced AKT and MAPK activation, indicative of an alternative mechanism underlying resistance. Conversely, depletion of CD79B sensitized primary refractory cells to ibrutinib and led to reduced phosphorylation of AKT or MAPK. Combination of the AKT inhibitor or the MAPK inhibitor with ibrutinib resulted in circumvention of both primary and acquired resistance in ABC-DLBCL. Our data collectively indicate that CD79B overexpression leading to activation of AKT/MAPK is a potential mechanism underlying primary ibrutinib resistance in ABC-DLBCL, and support its utility as an effective biomarker to predict therapeutic response to ibrutinib.
用依鲁替尼阻断B细胞受体信号通路为治疗B细胞恶性肿瘤提供了一种有前景的临床方法。然而，许多患者对该药物表现出原发性耐药或产生继发性耐药。在当前研究中，cDNA微阵列和蛋白质印迹分析显示，在对依鲁替尼表现出不同耐药性的活化B细胞样弥漫性大B细胞淋巴瘤（ABC-DLBCL）中，CD79B上调。CD79B的过表达足以诱导对依鲁替尼的耐药性，并增强AKT和MAPK的激活，这表明存在一种潜在的耐药机制。相反，CD79B的缺失使原发性难治性细胞对依鲁替尼敏感，并导致AKT或MAPK磷酸化减少。将AKT抑制剂或MAPK抑制剂与依鲁替尼联合使用可克服ABC-DLBCL中的原发性和获得性耐药。我们的数据共同表明，CD79B过表达导致AKT/MAPK激活是ABC-DLBCL中依鲁替尼原发性耐药的潜在机制，并支持其作为预测依鲁替尼治疗反应的有效生物标志物的效用。
