Bruton tyrosine kinase (BTK) links the B-cell antigen receptor (BCR) and Toll-like receptors with NF-κB. The role of BTK in primary central nervous system (CNS) lymphoma (PCNSL) is unknown. We performed a phase I clinical trial with ibrutinib, the first-in-class BTK inhibitor, for patients with relapsed or refractory CNS lymphoma. Clinical responses to ibrutinib occurred in 10 of 13 (77%) patients with PCNSL, including five complete responses. The only PCNSL with complete ibrutinib resistance harbored a mutation within the coiled-coil domain of CARD11, a known ibrutinib resistance mechanism. Incomplete tumor responses were associated with mutations in the B-cell antigen receptor-associated protein CD79B. CD79B-mutant PCNSLs showed enrichment of mammalian target of rapamycin (mTOR)-related gene sets and increased staining with PI3K/mTOR activation markers. Inhibition of the PI3K isoforms p110α/p110δ or mTOR synergized with ibrutinib to induce cell death in CD79B-mutant PCNSL cells.Significance: Ibrutinib has substantial activity in patients with relapsed or refractory B-cell lymphoma of the CNS. Response rates in PCNSL were considerably higher than reported for diffuse large B-cell lymphoma outside the CNS, suggesting a divergent molecular pathogenesis. Combined inhibition of BTK and PI3K/mTOR may augment the ibrutinib response in CD79B-mutant human PCNSLs. Cancer Discov; 7(9); 1018-29. ©2017 AACR.See related commentary by Lakshmanan and Byrd, p. 940This article is highlighted in the In This Issue feature, p. 920.

译文

布鲁顿酪氨酸激酶 (BTK) 将b细胞抗原受体 (BCR) 和Toll样受体与NF-κ B联系起来。BTK在原发性中枢神经系统 (CNS) 淋巴瘤 (PCNSL) 中的作用尚不清楚。我们使用ibrutinib (一流的BTK抑制剂) 对复发或难治性CNS淋巴瘤患者进行了I期临床试验。13例 (77% 例) PCNSL患者中有10例出现ibrutinib的临床反应,包括5例完全反应。唯一具有完全伊布替尼抗性的PCNSL在CARD11的卷曲螺旋结构域中具有突变,这是已知的伊布替尼抗性机制。不完全的肿瘤反应与b细胞抗原受体相关蛋白CD79B的突变有关。CD79B-mutant PCNSLs显示出哺乳动物雷帕霉素靶 (mTOR) 相关基因集的富集,并且PI3K/mTOR激活标记物的染色增加。抑制PI3K亚型p110α/p110δ 或mTOR与伊布替尼协同诱导CD79B-mutant PCNSL细胞死亡。意义: 伊布替尼在中枢神经系统复发或难治性b细胞淋巴瘤患者中具有重要活性。PCNSL的反应率大大高于CNS外弥漫性大b细胞淋巴瘤的报道,表明分子发病机制不同。BTK和PI3K/mTOR的联合抑制可能会增强CD79B-mutant人pcnsl中的伊布替尼反应。癌症椎间盘; 7(9); 1018-29。©2017 AACR。请参阅Lakshmanan和Byrd的相关评论,p。940本文在本刊功能第920页中突出显示。

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