Setiawan Syahru Agung, Liu Winston Zhenhao, Weng Pei-Wei, Lee Chia-Hwa, Yadav Vijesh Kumar, Hardianti Mardiah Suci, Yeh Chi-Tai, Chao Tsu-Yi
International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei City, 11031, Taiwan.
Human Biology, Revelle College, University of California, San Diego, USA.
Eur J Pharmacol. 2023 Mar 15;943:175526. doi: 10.1016/j.ejphar.2023.175526. Epub 2023 Jan 21.
Double-hit lymphoma (DHL) is an aggressive subset of Diffuse Large B-cell Lymphoma (DLBCL) with poor outcomes and without satisfying treatment options. BTK inhibitor monotherapy is ineffective to suppress aggressive lymphoma. Hence, combination with other potential agents is warranted. Here, we demonstrated the second generation of BTK inhibitor, zanubrutinib, and a BCL-2 inhibitor, navitoclax, worked in synergistic manner to suppress DHL. Comprehensive in silico approach by interrogating single-cell to bulk-level profiling was employed along with in vitro and in vivo validation in DHL cell lines. Ablation of BTK enhanced sensitivity to navitoclax and suppressed proliferation of DHL cells. Combination of second generation of BTK inhibitor with navitoclax synergistically suppressed DLBCL cells with higher synergy score in DHL subset. The drug combination triggered apoptosis and ferroptosis, with the latter being characterized by reactive oxygen species (ROS) accumulation, extensive lipid peroxidation, and depletion of reduced glutathione. Moreover, ablation of BTK sensitized DHL cells to ferroptosis. Mechanistically, disruption of BTK and BCL-2 triggered ferroptosis by downregulating NRF2 and HMOX1, while deactivating GPX4. Combination of zanubrutinib and navitoclax effectively suppressed tumor growth in vivo. Our data suggest that zanubrutinib and navitoclax synergistically suppressed DHL by inducing apoptosis and ferroptosis.
双打击淋巴瘤（DHL）是弥漫性大B细胞淋巴瘤（DLBCL）的侵袭性亚型，预后较差且缺乏令人满意的治疗方案。BTK抑制剂单药治疗对抑制侵袭性淋巴瘤无效。因此，与其他潜在药物联合使用是必要的。在此，我们证明第二代BTK抑制剂泽布替尼和BCL-2抑制剂维奈克拉以协同方式抑制DHL。通过询问单细胞到批量水平的分析，采用了全面的计算机方法，并在DHL细胞系中进行了体外和体内验证。BTK的缺失增强了对维奈克拉的敏感性，并抑制了DHL细胞的增殖。第二代BTK抑制剂与维奈克拉联合使用可协同抑制DLBCL细胞，在DHL亚组中具有更高的协同评分。该药物组合引发凋亡和铁死亡，后者的特征是活性氧（ROS）积累、广泛的脂质过氧化和还原型谷胱甘肽的消耗。此外，BTK的缺失使DHL细胞对铁死亡敏感。从机制上讲，BTK和BCL-2的破坏通过下调NRF2和HMOX1，同时使GPX4失活来引发铁死亡。泽布替尼和维奈克拉联合使用可有效抑制体内肿瘤生长。我们的数据表明，泽布替尼和维奈克拉通过诱导凋亡和铁死亡协同抑制DHL。
