Purpose: Bcl-2 has been effectively targeted in lymphoid malignancies. However, resistance is inevitable, and novel approaches to target mitochondrial apoptosis are necessary. AZD5991, a selective BH3-mimetic in clinical trials, inhibits Mcl-1 with high potency. Experimental Design: We explored the preclinical activity of AZD5991 in diffuse large B-cell lymphoma (DLBCL) and ibrutinib-resistant mantle cell lymphoma (MCL) cell lines, MCL patient samples, and mice bearing DLBCL and MCL xenografts using flow cytometry, immunoblotting, and Seahorse respirometry assay. Cas9 gene editing and ex vivo functional drug screen assays helped identify mechanisms of resistance to Mcl-1 inhibition. Results: Mcl-1 was expressed in DLBCL and MCL cell lines and primary tumors. Treatment with AZD5991 restricted growth of DLBCL cells independent of cell of origin and overcame ibrutinib resistance in MCL cells. Mcl-1 inhibition led to mitochondrial dysfunction as manifested by mitochondrial membrane depolarization, decreased mitochondrial mass, and induction of mitophagy. This was accompanied by impairment of oxidative phosphorylation. TP53 and BAX were essential for sensitivity to Mcl-1, and oxidative phosphorylation was implicated in resistance to Mcl-1 inhibition. Induction of prosurvival proteins (e.g., Bcl-xL) in stromal conditions that mimic the tumor microenvironment rendered protection of primary MCL cells from Mcl-1 inhibition, while BH3-mimetics targeting Bcl-2/xL sensitized lymphoid cells to AZD5991. Treatment with AZD5991 reduced tumor growth in murine lymphoma models and prolonged survival of MCL PDX mice. Conclusions: Selective targeting Mcl-1 is a promising therapeutic approach in lymphoid malignancies. TP53 apoptotic network and metabolic reprogramming underlie susceptibility to Mcl-1 inhibition.

中文翻译：

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Mcl-1 的药理学靶向以 TP53 和 BAX 依赖性方式诱导 B 细胞淋巴瘤细胞的线粒体功能障碍和细胞凋亡

目的：Bcl-2 已被有效靶向淋巴恶性肿瘤。然而，抵抗是不可避免的，并且需要针对线粒体细胞凋亡的新方法。AZD5991 是临床试验中的一种选择性 BH3 模拟物，可高效抑制 Mcl-1。实验设计：我们使用流式细胞术、免疫印迹、和海马呼吸测定法。Cas9 基因编辑和体外功能性药物筛选分析有助于确定对 Mcl-1 抑制的耐药机制。结果：Mcl-1 在 DLBCL 和 MCL 细胞系和原发性肿瘤中表达。AZD5991 治疗限制了 DLBCL 细胞的生长，与来源细胞无关，并克服了 MCL 细胞中的依鲁替尼耐药性。Mcl-1 抑制导致线粒体功能障碍，表现为线粒体膜去极化、线粒体质量下降和线粒体自噬的诱导。这伴随着氧化磷酸化的损害。TP53 和 BAX 对于对 Mcl-1 的敏感性至关重要，氧化磷酸化与对 Mcl-1 抑制的抗性有关。在模拟肿瘤微环境的基质条件下诱导促存活蛋白（例如 Bcl-xL）可保护原代 MCL 细胞免受 Mcl-1 抑制，而靶向 Bcl-2/xL 的 BH3 模拟物可使淋巴样细胞对 AZD5991 敏感。用 AZD5991 治疗可减少小鼠淋巴瘤模型中的肿瘤生长并延长 MCL PDX 小鼠的存活期。结论：选择性靶向 Mcl-1 是一种很有前途的淋巴恶性肿瘤治疗方法。TP53 凋亡网络和代谢重编程是对 Mcl-1 抑制易感性的基础。