Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York 10065, USA.
Clin Cancer Res. 2010 Jan 15;16(2):587-99. doi: 10.1158/1078-0432.CCR-09-1519. Epub 2010 Jan 12.
B-cell receptor signaling plays an important role in the pathogenesis of chronic lymphocytic leukemia (CLL). However, blocking B-cell receptor signaling with dasatinib, an inhibitor of SRC kinase, produced variable results in preclinical and clinical studies. We aim to define the molecular mechanisms underlying the differential dasatinib sensitivity and to uncover more effective therapeutic targets in CLL.
Fresh CLL B cells were treated with dasatinib, and cell viability was followed. The CLL cases were then divided into good and poor responders. The cellular response was correlated with the activities of B-cell receptor signaling molecules, as well as with molecular and cytogenetic prognostic factors.
Among 50 CLL cases, dasatinib treatment reduced cell viability by 2% to 90%, with an average reduction of 47% on day 4 of culture. The drug induced CLL cell death through the intrinsic apoptotic pathway mediated by reactive oxygen species. Unexpectedly, phosphorylation of SRC family kinases was inhibited by dasatinib in good, as well as poor, responders. As opposed to SRC family kinases, activities of two downstream molecules, SYK and phospholipase Cgamma2, correlate well with the apoptotic response of CLL cells to dasatinib.
Thus, SYK inhibition predicts cellular response to dasatinib. SYK, together with phospholipase Cgamma2, may serve as potential biomarkers to predict dasatinib therapeutic response in patients. From the pathogenic perspective, our study suggests the existence of alternative mechanisms or pathways that activate SYK, independent of SRC kinase activities. The study further implicates that SYK might serve as a more effective therapeutic target in CLL treatment.
B 细胞受体信号在慢性淋巴细胞白血病（CLL）的发病机制中起着重要作用。然而，用 SRC 激酶抑制剂达沙替尼阻断 B 细胞受体信号在临床前和临床研究中产生了不同的结果。我们旨在确定导致达沙替尼敏感性差异的分子机制，并发现 CLL 中更有效的治疗靶点。
新鲜的 CLL B 细胞用达沙替尼处理，并检测细胞活力。然后将 CLL 病例分为良好和不良反应者。细胞反应与 B 细胞受体信号分子的活性以及分子和细胞遗传学预后因素相关。
在 50 例 CLL 病例中，达沙替尼处理使细胞活力降低了 2%至 90%，培养第 4 天的平均降低了 47%。该药物通过活性氧介导的内在凋亡途径诱导 CLL 细胞死亡。出乎意料的是，达沙替尼在良好和不良反应者中均抑制了 SRC 家族激酶的磷酸化。与 SRC 家族激酶相反，两种下游分子 SYK 和磷脂酶 Cγ2 的活性与 CLL 细胞对达沙替尼的凋亡反应密切相关。
因此，SYK 抑制预测了 CLL 细胞对达沙替尼的反应。SYK 与磷脂酶 Cγ2 一起可作为潜在的生物标志物，用于预测患者对达沙替尼的治疗反应。从发病机制的角度来看，我们的研究表明存在激活 SYK 的替代机制或途径，独立于 SRC 激酶活性。该研究进一步表明，SYK 可能成为 CLL 治疗中更有效的治疗靶点。
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