Substitution scanning identifies a novel, catalytically active ibrutinib-resistant BTK cysteine 481 to threonine (C481T) variant.
Substitution scanning identifies a novel, catalytically active ibrutinib-resistant BTK cysteine 481 to threonine (C481T) variant.
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不可逆布鲁顿酪氨酸激酶 (BTK) 抑制剂 ibrutinib 和 acalabrutinib 在多种 B 细胞恶性肿瘤中表现出显着的临床反应。已经在一个患者亚群中发现了获得性耐药，其中影响 BTK 的突变主要将激酶结构域中的半胱氨酸 481 替换为催化活性丝氨酸，从而消除抑制剂的共价结合。相反，激活 BTK 底物磷脂酶 Cγ2 (PLCγ2) 中的取代会赋予独立于 BTK 的耐药性。在此，除了需要两个核苷酸取代的苏氨酸之外，我们还由于半胱氨酸 481 密码子的单核苷酸改变而产生了所有六种可能的氨基酸取代，并进行了功能分析。精氨酸、苯丙氨酸、色氨酸或酪氨酸的替代使催化活性完全失活，而甘氨酸的替代则造成严重损害。苏氨酸取代的 BTK 具有催化活性，类似于丝氨酸取代。我们确定了半胱氨酸 481 替代的三种潜在的依鲁替尼耐药情况：(1) 丝氨酸，具有催化活性，因此在患者中占主导地位。 (2) 苏氨酸，也具有催化活性，但预计很稀缺，因为需要两个核苷酸变化。 (3)由于被其他残基取代的BTK变体没有催化活性，因此可能需要补偿性突变，因此非常稀缺。甘氨酸和色氨酸变体尚未报道，但可能也提供抗性。
Irreversible Bruton tyrosine kinase (BTK) inhibitors, ibrutinib and acalabrutinib have demonstrated remarkable clinical responses in multiple B-cell malignancies. Acquired resistance has been identified in a sub-population of patients in which mutations affecting BTK predominantly substitute cysteine 481 in the kinase domain for catalytically active serine, thereby ablating covalent binding of inhibitors. Activating substitutions in the BTK substrate phospholipase Cγ2 (PLCγ2) instead confers resistance independent of BTK. Herein, we generated all six possible amino acid substitutions due to single nucleotide alterations for the cysteine 481 codon, in addition to threonine, requiring two nucleotide substitutions, and performed functional analysis. Replacement by arginine, phenylalanine, tryptophan or tyrosine completely inactivated the catalytic activity, whereas substitution with glycine caused severe impairment. BTK with threonine replacement was catalytically active, similar to substitution with serine. We identify three potential ibrutinib resistance scenarios for cysteine 481 replacement: (1) Serine, being catalytically active and therefore predominating among patients. (2) Threonine, also being catalytically active, but predicted to be scarce, because two nucleotide changes are needed. (3) As BTK variants replaced with other residues are catalytically inactive, they presumably need compensatory mutations, therefore being very scarce. Glycine and tryptophan variants were not yet reported but likely also provide resistance.
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