Mechanisms of Resistance to Noncovalent Bruton's Tyrosine Kinase Inhibitors.
Mechanisms of Resistance to Noncovalent Bruton's Tyrosine Kinase Inhibitors.
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DOI：
10.1056/nejmoa2114110
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发表时间：
2022-02-24
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共价（不可逆）布鲁顿酪氨酸激酶（BTK）抑制剂已经改变了多种B细胞癌症，特别是慢性淋巴细胞白血病（CLL）的治疗。然而，耐药性可通过多种机制产生，包括在共价BTK抑制剂的结合位点残基C481处的BTK获得性突变。非共价（可逆）BTK抑制剂克服了这一机制和其他耐药来源，但目前对这些疗法的耐药机制还不清楚。我们对治疗前标本以及疾病进展时从接受非共价BTK抑制剂吡托替尼治疗的CLL患者中获得的标本进行了基因组分析。进行结构建模、BTK结合测定和基于细胞的测定以研究赋予对非共价BTK抑制剂的抗性的突变。在55名接受治疗的患者中，我们确定了9名复发性或难治性CLL患者，并获得了对吡托替尼的遗传耐药机制。我们发现突变（V416 L、A428 D、M437 R、T474 I和L528 W）聚集在BTK的激酶结构域中，并赋予对非共价BTK抑制剂和某些共价BTK抑制剂的抗性。所有9例患者均发现BTK或BTK信号分子和下游底物磷脂酶C γ 2（PLCγ2）突变。尽管继续使用非共价BTK抑制剂治疗，但反映B细胞受体信号传导的转录活化持续存在。对非共价BTK抑制剂的耐药性是通过靶向BTK突变和下游PLCγ2突变产生的，这些突变允许逃避BTK抑制。这些突变中的一部分也赋予了对临床批准的共价BTK抑制剂的耐药性。这些数据表明了基因组从已建立的共价和新型非共价BTK抑制剂逃逸的新机制。（由美国血液学会和其他机构资助。
Covalent (irreversible) Bruton’s tyrosine kinase (BTK) inhibitors have transformed the treatment of multiple B-cell cancers, especially chronic lymphocytic leukemia (CLL). However, resistance can arise through multiple mechanisms, including acquired mutations in BTK at residue C481, the binding site of covalent BTK inhibitors. Noncovalent (reversible) BTK inhibitors overcome this mechanism and other sources of resistance, but the mechanisms of resistance to these therapies are currently not well understood. We performed genomic analyses of pretreatment specimens as well as specimens obtained at the time of disease progression from patients with CLL who had been treated with the noncovalent BTK inhibitor pirtobrutinib. Structural modeling, BTK-binding assays, and cell-based assays were conducted to study mutations that confer resistance to noncovalent BTK inhibitors. Among 55 treated patients, we identified 9 patients with relapsed or refractory CLL and acquired mechanisms of genetic resistance to pirtobrutinib. We found mutations (V416L, A428D, M437R, T474I, and L528W) that were clustered in the kinase domain of BTK and that conferred resistance to both noncovalent BTK inhibitors and certain covalent BTK inhibitors. Mutations in BTK or phospholipase C gamma 2 (PLCγ2), a signaling molecule and downstream substrate of BTK, were found in all 9 patients. Transcriptional activation reflecting B-cell–receptor signaling persisted despite continued therapy with noncovalent BTK inhibitors. Resistance to noncovalent BTK inhibitors arose through on-target BTK mutations and downstream PLCγ2 mutations that allowed escape from BTK inhibition. A proportion of these mutations also conferred resistance across clinically approved covalent BTK inhibitors. These data suggested new mechanisms of genomic escape from established covalent and novel noncovalent BTK inhibitors. (Funded by the American Society of Hematology and others.)