Dana Farber Cancer Institute, Boston, Massachusetts, USA.
Harvard Medical School, Boston, Massachusetts, USA.
Br J Haematol. 2024 Nov;205(5):1866-1872. doi: 10.1111/bjh.19756. Epub 2024 Sep 18.
Covalent Bruton's tyrosine kinase-inhibitors (cBTK-i) are highly active in MYD88-mutated (MYD88) Waldenstrom's macroglobulinaemia and suppress nuclear factor kappa-light-chain-enhancer of activated B cells and extracellular signal-regulated kinases-1/2 (ERK1/2)-related signalling. BTK mutations are associated with cBTK-i acquired resistance and are accompanied by reactivation of ERK1/2 that promotes inflammatory cytokine secretion and paracrine-mediated resistance of BTK wild-type (BTK) tumour cells. Pirtobrutinib is a non-covalent BTK-inhibitor that binds at non-BTK sites. We show that pirtobrutinib blocked p-ERK1/2, ERK1/2-driven inflammatory cytokines, and overcame paracrine-mediated resistance in MYD88 lymphoma cells expressing mutated BTK. Our results provide important mechanistic insights for the activity of pirtobrutinib in MYD88 lymphomas carrying BTK mutations.
共价布鲁顿酪氨酸激酶抑制剂（cBTK-i）在 MYD88 突变（MYD88）华氏巨球蛋白血症中具有高度活性，可抑制核因子κ轻链增强子的活化 B 细胞和细胞外信号调节激酶 1/2（ERK1/2）相关信号转导。BTK 突变与 cBTK-i 获得性耐药相关，并伴有 ERK1/2 的重新激活，促进炎症细胞因子的分泌和旁分泌介导的 BTK 野生型（BTK）肿瘤细胞耐药。Pirtobrutinib 是一种非共价 BTK 抑制剂，与非 BTK 位点结合。我们表明，pirtobrutinib 阻断了 p-ERK1/2、ERK1/2 驱动的炎症细胞因子，并克服了表达突变 BTK 的 MYD88 淋巴瘤细胞中的旁分泌介导的耐药性。我们的结果为 pirtobrutinib 在携带 BTK 突变的 MYD88 淋巴瘤中的活性提供了重要的机制见解。
