Identification of a structurally novel BTK mutation that drives ibrutinib resistance in CLL.
Identification of a structurally novel BTK mutation that drives ibrutinib resistance in CLL.
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DOI：
10.18632/oncotarget.11932
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发表时间：
2016-10-18
期刊：
影响因子：
--
通讯作者：
Wang YL
中科院分区：
文献类型：
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作者：
Sharma S;Galanina N;Guo A;Lee J;Kadri S;Van Slambrouck C;Long B;Wang W;Ming M;Furtado LV;Segal JP;Stock W;Venkataraman G;Tang WJ;Lu P;Wang YL
伊布鲁替尼(ibrutinib，IBR)是一种一流的Bruton酪氨酸激酶(BTK)抑制剂，在复发/难治和治疗初治的慢性淋巴细胞白血病(CLL)中均显示出很高的应答率。然而，大约25%的患者在20个月的中位随访期内停止了伊布鲁替尼治疗，许多患者由于白血病进展或里希特转化而停止治疗。影响BTK的C481残基的突变破坏了ibrutinib的结合，并被我们和其他人描述为ibrutinib耐药的最常见机制。到目前为止，所有已描述的BTK突变都位于其激酶区域，而该区域以外的突变从未被描述过。在此，我们报告一例慢性淋巴细胞性白血病进展，经伊布鲁替尼抢救后复发。对患者整个临床过程中的样本进行的一系列分析发现，Bruton酪氨酸激酶的SH2结构域中存在一种新的结构突变(BTKT316A)，而不是与疾病复发有关的激酶结构域。在功能上，携带BTKT316A的细胞在细胞和分子水平上对伊布鲁替尼的抗性程度与BTKC481S相似。我们的研究进一步深入了解了伊布鲁替尼耐药的不同机制，这对开发下一代BTK抑制剂以及检测复发患者的突变具有重要意义。
Ibrutinib (ibr), a first-in-class Bruton tyrosine kinase (BTK) inhibitor, has demonstrated high response rates in both relapsed/refractory and treatment naïve chronic lymphocytic leukemia (CLL). However, about 25% of patients discontinue ibrutinib therapy at a median follow-up of 20 months and many patients discontinue the treatment due to leukemia progression or Richter transformation. Mutations affecting the C481 residue of BTK disrupt ibrutinib binding and have been characterized by us and others as the most common mechanism of ibrutinib resistance. Thus far, all described BTK mutations are located in its kinase domain and mutations outside this domain have never been described. Herein, we report a patient whose CLL progressed, was salvaged with ibrutinib and then relapsed. Serial analysis of samples throughout patient's clinical course identified a structurally novel mutation (BTKT316A) in the SH2 domain, but not kinase domain, of Bruton tyrosine kinase which was associated with disease relapse. Functionally, cells carrying BTKT316A show resistance to ibrutinib at both cellular and molecular levels to a similar extent as BTKC481S. Our study lends further insight into the diverse mechanisms of ibrutinib resistance that has important implications for the development of next-generation BTK inhibitors as well as mutation detection in relapsed patients.