Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib.
Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib.
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DOI：
10.1056/nejmoa1400029
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发表时间：
2014-06-12
期刊：
影响因子：
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通讯作者：
Byrd JC
中科院分区：
文献类型：
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作者：
Woyach JA;Furman RR;Liu TM;Ozer HG;Zapatka M;Ruppert AS;Xue L;Li DH;Steggerda SM;Versele M;Dave SS;Zhang J;Yilmaz AS;Jaglowski SM;Blum KA;Lozanski A;Lozanski G;James DF;Barrientos JC;Lichter P;Stilgenbauer S;Buggy JJ;Chang BY;Johnson AJ;Byrd JC
伊布鲁替尼是一种不可逆转的布鲁顿氏酪氨酸激酶(BTK)抑制剂，对慢性淋巴细胞白血病(CLL)有效。对不可逆激酶抑制剂的耐药性和与BTK抑制相关的耐药性尚未被表征。虽然只有一小部分患者在伊布鲁替尼治疗期间复发，但了解耐药机制是重要的。我们评估了复发疾病的患者，以确定可能介导伊布鲁替尼耐药性的突变。我们对6例对伊布鲁替尼治疗产生获得性耐药的患者的样本进行了基线和复发时间的全外显子组测序。然后，我们对已识别的突变进行了功能分析。此外，我们对9名淋巴细胞增多症患者的样本进行了离子激流测序，以确定耐药突变。我们在5名患者中发现了伊布鲁替尼结合部位BTK的半胱氨酸到丝氨酸突变，并在2名患者中发现了PLCγ2的三个不同的突变。功能分析表明，BTK的C481S突变导致了一种只能被伊布鲁替尼可逆抑制的蛋白质。PLCγ2中的R665W和L845F突变都是导致自主B细胞受体活性的潜在功能获得突变。在服用伊布鲁替尼的淋巴细胞增多症患者中，没有发现这些突变。对不可逆的BTK抑制剂ibrutinib的耐药性通常涉及发生ibrutinib结合的半胱氨酸残基的突变。这一发现，再加上Btk下游的另外两个PLCγ2突变，强调了B细胞受体途径在伊布鲁替尼治疗慢性淋巴细胞性白血病的作用机制中的重要性。(由国家癌症研究所和其他机构资助。)
Ibrutinib is an irreversible inhibitor of Bruton’s tyrosine kinase (BTK) and is effective in chronic lymphocytic leukemia (CLL). Resistance to irreversible kinase inhibitors and resistance associated with BTK inhibition have not been characterized. Although only a small proportion of patients have had a relapse during ibrutinib therapy, an understanding of resistance mechanisms is important. We evaluated patients with relapsed disease to identify mutations that may mediate ibrutinib resistance. We performed whole-exome sequencing at baseline and the time of relapse on samples from six patients with acquired resistance to ibrutinib therapy. We then performed functional analysis of identified mutations. In addition, we performed Ion Torrent sequencing for identified resistance mutations on samples from nine patients with prolonged lymphocytosis. We identified a cysteine-to-serine mutation in BTK at the binding site of ibrutinib in five patients and identified three distinct mutations in PLCγ2 in two patients. Functional analysis showed that the C481S mutation of BTK results in a protein that is only reversibly inhibited by ibrutinib. The R665W and L845F mutations in PLCγ2 are both potentially gain-of-function mutations that lead to autonomous B-cell–receptor activity. These mutations were not found in any of the patients with prolonged lymphocytosis who were taking ibrutinib. Resistance to the irreversible BTK inhibitor ibrutinib often involves mutation of a cysteine residue where ibrutinib binding occurs. This finding, combined with two additional mutations in PLCγ2 that are immediately downstream of BTK, underscores the importance of the B-cell–receptor pathway in the mechanism of action of ibrutinib in CLL. (Funded by the National Cancer Institute and others.)