Saba Nakhle S, Wong Deanna H, Tanios Georges, Iyer Jessica R, Lobelle-Rich Patricia, Dadashian Eman L, Liu Delong, Fontan Lorena, Flemington Erik K, Nichols Cydney M, Underbayev Chingiz, Safah Hana, Melnick Ari, Wiestner Adrian, Herman Sarah E M
Section of Hematology and Medical Oncology, Department of Medicine, Tulane University, New Orleans, Louisiana.
Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland.
Cancer Res. 2017 Dec 15;77(24):7038-7048. doi: 10.1158/0008-5472.CAN-17-2485. Epub 2017 Oct 9.
The clinical efficacy displayed by ibrutinib in chronic lymphocytic leukemia (CLL) has been challenged by the frequent emergence of resistant clones. The ibrutinib target, Bruton's tyrosine kinase (BTK), is essential for B-cell receptor signaling, and most resistant cases carry mutations in or , a downstream effector target of BTK. Recent findings show that MI-2, a small molecule inhibitor of the para-caspase MALT1, is effective in preclinical models of another type of BCR pathway-dependent lymphoma. We therefore studied the activity of MI-2 against CLL and ibrutinib-resistant CLL. Treatment of CLL cells with MI-2 inhibited MALT1 proteolytic activity reduced BCR and NF-κB signaling, inhibited nuclear translocation of RelB and p50, and decreased Bcl-xL levels. MI-2 selectively induced dose and time-dependent apoptosis in CLL cells, sparing normal B lymphocytes. Furthermore, MI-2 abrogated survival signals provided by stromal cells and BCR cross-linking and was effective against CLL cells harboring features associated with poor outcomes, including 17p deletion and unmutated Notably, MI-2 was effective against CLL cells collected from patients harboring mutations conferring resistance to ibrutinib. Overall, our findings provide a preclinical rationale for the clinical development of MALT1 inhibitors in CLL, in particular for ibrutinib-resistant forms of this disease. .
依鲁替尼在慢性淋巴细胞白血病（CLL）中显示出的临床疗效受到耐药克隆频繁出现的挑战。依鲁替尼的靶点布鲁顿酪氨酸激酶（BTK）对B细胞受体信号传导至关重要，大多数耐药病例在BTK的下游效应靶点 或 中携带突变。最近的研究发现表明，对旁半胱天冬酶MALT1具有抑制作用的小分子MI-2在另一种BCR途径依赖性淋巴瘤的临床前模型中具有疗效。因此，我们研究了MI-2对CLL及依鲁替尼耐药CLL的活性。用MI-2处理CLL细胞可抑制MALT1的蛋白水解活性，降低BCR和NF-κB信号传导，抑制RelB和p50的核转位，并降低Bcl-xL水平。MI-2在CLL细胞中选择性地诱导剂量和时间依赖性凋亡，而对正常B淋巴细胞无影响。此外，MI-2消除了基质细胞提供的生存信号以及BCR交联，并对具有不良预后特征的CLL细胞有效，包括17p缺失和未突变的 。值得注意的是，MI-2对从携带对依鲁替尼耐药突变的患者中收集的CLL细胞有效。总体而言，我们的研究结果为MALT1抑制剂在CLL中的临床开发提供了临床前理论依据，特别是针对这种疾病的依鲁替尼耐药形式。
