Pan-SRC kinase inhibition blocks B-cell receptor oncogenic signaling in non-Hodgkin lymphoma
Pan-SRC kinase inhibition blocks B-cell receptor oncogenic signaling in non-Hodgkin lymphoma
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DOI：
10.1182/blood-2017-10-809210
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发表时间：
2018-05-24
期刊：
影响因子：
20.3
通讯作者：
Oricchio, Elisa
中科院分区：
文献类型：
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作者：
Battistello, Elena;Katanayeva, Natalya;Oricchio, Elisa
在弥漫性大B细胞淋巴瘤（DLBCL）中，B细胞受体（BCR）的激活促进了多种致癌信号，这对肿瘤增殖至关重要。抑制BCR下游靶点布鲁顿酪氨酸激酶（BTK）仅在DLBCL患者亚组中有效。在这里，我们使用从DLBCL患者中分离的淋巴瘤细胞来测量靶向治疗对BCR信号传导的影响并预测反应。在对BTK抑制耐药的淋巴瘤中，我们发现阻断BTK活性增强了肿瘤对BCR下游替代致癌信号的依赖性，集中在MYC上调上。为了完全消除BCR的活性，我们在遗传上和免疫抑制了SRC激酶林恩、FYN和BLK的活性，它们负责BCR信号的传播。这些激酶的抑制强烈降低了源自DLBCL患者的异种移植物和细胞系中的肿瘤生长，而不依赖于其分子亚型，从而提高了成为广泛和多样化DLBCL患者组中相关治疗靶点的可能性。
In diffuse large B-cell lymphoma (DLBCL), activation of the B-cell receptor (BCR) promotes multiple oncogenic signals, which are essential for tumor proliferation. Inhibition of the Bruton's tyrosine kinase (BTK), a BCR downstream target, is therapeutically effective only in a subgroup of patients with DLBCL. Here, we used lymphoma cells isolated from patients with DLBCL to measure the effects of targeted therapies on BCR signaling and to anticipate response. In lymphomas resistant to BTK inhibition, we show that blocking BTK activity enhanced tumor dependencies from alternative oncogenic signals downstream of the BCR, converging on MYC upregulation. To completely ablate the activity of the BCR, we genetically and pharmacologically repressed the activity of the SRC kinases LYN, FYN, and BLK, which are responsible for the propagation of the BCR signal. Inhibition of these kinases strongly reduced tumor growth in xenografts and cell lines derived from patients with DLBCL independent of their molecular subtype, advancing the possibility to be relevant therapeutic targets in broad and diverse groups of DLBCL patients.