The B-cell receptor and the phosphatidylinositol 3-kinase (PI3K) signalling pathways, together with their downstream partners, represent important therapeutic targets for B-cell lymphomas. Here, we evaluated the activity of acalabrutinib (ACP-196) and ACP-319 (AMG-319), second generation inhibitors of Bruton tyrosine kinase (BTK) and PI3Kδ inhibitor, respectively, in lymphoma pre-clinical models. The two compounds showed activity in activated B-cell-like diffuse large B-cell lymphoma (ABC DLBCL), mantle cell lymphoma and marginal zone lymphoma. Two in vivo experiments with ABC DLBCL and MCL xenografts confirmed the effect of the single agents. Benefit was achieved by exposing the lymphoma cell lines to both acalabrutinib and ACP-319. Two cell lines presented a discordant response to first and second generation BTK inhibitors, probably due to the inhibition by ibrutinib of kinases other than BTK. In conclusion, our data sustain the on-going current trials with acalabrutinib and ACP-319 as single agents and provide the basis for the investigation of their combination as well.

中文翻译：

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acalabrutinib和ACP-319在侵袭性淋巴瘤的临床前模型中对BTK和PI3Kδ的单一和联合抑制作用。

B细胞受体和磷脂酰肌醇3-激酶（PI3K）信号传导途径以及其下游伴侣代表了B细胞淋巴瘤的重要治疗靶标。在这里，我们评估了淋巴瘤临床前模型中第二代布鲁顿酪氨酸激酶抑制剂（BTK）和PI3Kδ抑制剂acalabrutinib（ACP-196）和ACP-319（AMG-319）的活性。这两种化合物在活化的B细胞样弥漫性大B细胞淋巴瘤（ABC DLBCL），套细胞淋巴瘤和边缘区淋巴瘤中均具有活性。用ABC DLBCL和MCL异种移植物进行的两个体内实验证实了单一药物的作用。通过将淋巴瘤细胞系同时暴露于acalabrutinib和ACP-319可获得益处。两种细胞系对第一代和第二代BTK抑制剂的反应不一致，可能是由于依鲁替尼抑制了BTK以外的其他激酶。总之，我们的数据支持了acalabrutinib和ACP-319作为单一药物的正在进行的当前试验，并为研究它们的组合提供了基础。