Tandler Claudia, Schmidt Moritz, Heitmann Jonas S, Hierold Julia, Schmidt Jonas, Schneider Pascal, Dörfel Daniela, Walz Juliane, Salih Helmut R
Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Department of Internal Medicine, University Hospital Tuebingen, 72076 Tuebingen, Germany.
Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland.
Cancers (Basel). 2020 Sep 23;12(10):2725. doi: 10.3390/cancers12102725.
The introduction of idelalisib, ibrutinib and venetoclax for treatment of chronic lymphocytic leukemia (CLL) has greatly improved long term survival of patients. However, many patients do not achieve complete remission and suffer from development of resistance upon treatment with these small molecule inhibitors. Here we report that the TNF family member B-cell activating factor (BAFF) mediates resistance of CLL cells to idelalisib, ibrutinib and venetoclax by sustaining survival and preventing apoptosis of the malignant B cells as revealed by analysis of cellular ATP levels and mitochondrial membrane integrity as well as caspase activation, respectively. As BAFF also plays a prominent role in autoimmune diseases, the BAFF-neutralizing antibody belimumab was developed and approved for treatment of systemic lupus erythematosus (SLE). When we employed belimumab in the context of CLL treatment with idelalisib, ibrutinib and venetoclax, BAFF neutralization was found to significantly increase the sensitivity of the leukemic cells to all three small molecule inhibitors. Notably, BAFF neutralization proved to be beneficial independently of clinical stage according to Binet and Rai or IgVH mutational status. Our results identify drug repurposing of belimumab for neutralization of BAFF to complement small molecule inhibitor treatment as a promising therapeutic approach in CLL that is presently undergoing clinical evaluation.
idelalisib、ibrutinib和venetoclax用于治疗慢性淋巴细胞白血病（CLL）极大地提高了患者的长期生存率。然而，许多患者并未实现完全缓解，并且在使用这些小分子抑制剂治疗时会产生耐药性。在此我们报告，TNF家族成员B细胞活化因子（BAFF）通过维持恶性B细胞的存活并防止其凋亡，介导CLL细胞对idelalisib、ibrutinib和venetoclax的耐药性，这分别通过细胞ATP水平分析、线粒体膜完整性分析以及半胱天冬酶激活得以揭示。由于BAFF在自身免疫性疾病中也起着重要作用，BAFF中和抗体贝利尤单抗已被研发并获批用于治疗系统性红斑狼疮（SLE）。当我们在使用idelalisib、ibrutinib和venetoclax治疗CLL的背景下使用贝利尤单抗时，发现BAFF中和可显著提高白血病细胞对所有三种小分子抑制剂的敏感性。值得注意的是，根据比内特（Binet）和赖（Rai）分期或免疫球蛋白重链可变区（IgVH）突变状态，BAFF中和被证明无论临床分期如何均有益处。我们的结果表明，将贝利尤单抗重新用于中和BAFF以补充小分子抑制剂治疗，是目前正在进行临床评估的一种有前景的CLL治疗方法。
