Kozaki Ryohei, Vogler Meike, Walter Harriet S, Jayne Sandrine, Dinsdale David, Siebert Reiner, Dyer Martin J S, Yoshizawa Toshio
Department of Molecular and Cell Biology, University of Leicester, Leicester LE1 7RH, UK.
Ono Pharmaceutical Co. Ltd., Osaka 618-8585, Japan.
Cancers (Basel). 2018 Apr 23;10(4):127. doi: 10.3390/cancers10040127.
Bruton's tyrosine kinase (BTK) is a key regulator of the B-cell receptor signaling pathway, and aberrant B-cell receptor (BCR) signaling has been implicated in the survival of malignant B-cells. However, responses of the diffuse large B-cell lymphoma (DLBCL) to inhibitors of BTK (BTKi) are infrequent, highlighting the need to identify mechanisms of resistance to BTKi as well as predictive biomarkers. We investigated the response to the selective BTKi, tirabrutinib, in a panel of 64 hematopoietic cell lines. Notably, only six cell lines were found to be sensitive. Although activated B-cell type DLBCL cells were most sensitive amongst all cell types studied, sensitivity to BTKi did not correlate with the presence of activating mutations in the BCR pathway. To improve efficacy of tirabrutinib, we investigated combination strategies with 43 drugs inhibiting 34 targets in six DLBCL cell lines. Based on the results, an activated B-cell-like (ABC)-DLBCL cell line, TMD8, was the most sensitive cell line to those combinations, as well as tirabrutinib monotherapy. Furthermore, tirabrutinib in combination with idelalisib, palbociclib, or trametinib was more effective in TMD8 with acquired resistance to tirabrutinib than in the parental cells. These targeted agents might be usefully combined with tirabrutinib in the treatment of ABC-DLBCL.
布鲁顿酪氨酸激酶（BTK）是B细胞受体信号通路的关键调节因子，异常的B细胞受体（BCR）信号传导与恶性B细胞的存活有关。然而，弥漫性大B细胞淋巴瘤（DLBCL）对BTK抑制剂（BTKi）的反应并不常见，这凸显了识别对BTKi耐药机制以及预测性生物标志物的必要性。我们在一组64种造血细胞系中研究了对选择性BTKi——替拉鲁替尼的反应。值得注意的是，仅发现六种细胞系敏感。尽管在所有研究的细胞类型中，活化B细胞型DLBCL细胞最为敏感，但对BTKi的敏感性与BCR途径中激活突变的存在无关。为提高替拉鲁替尼的疗效，我们在六种DLBCL细胞系中研究了与43种抑制34个靶点的药物的联合策略。基于这些结果，一种活化B细胞样（ABC）-DLBCL细胞系TMD8对这些联合方案以及替拉鲁替尼单药治疗最为敏感。此外，替拉鲁替尼与idelalisib、帕博西尼或曲美替尼联合使用时，在对替拉鲁替尼产生获得性耐药的TMD8细胞中比在亲代细胞中更有效。这些靶向药物可能与替拉鲁替尼联合用于ABC-DLBCL的治疗。
