靶向恶性肿瘤的组合疗法旨在提高治疗效果并减少毒性。去甲基化药物5-Aza-2'-deoxycytidine（5-Aza-2'）通过困住DNMT1引起DNA蛋白交联，从而增强肿瘤抑制基因的转录并诱导复制错误。SUMO的翻译后修饰在DNA损伤应答中发挥重要作用，并且需要DNMT1的陷入分解。在这里，我们将SUMOylation抑制剂TAK981和DNA去甲基化剂5-Aza-2'-deoxycytidine结合起来，以改善MYC驱动的造血恶性肿瘤的治疗效果，因为MYC过表达的肿瘤对SUMOylation抑制敏感。我们研究了经典的MYC驱动的淋巴瘤伯基特淋巴瘤，以及有或没有MYC易位的弥漫性大B细胞淋巴瘤（DLBCL）。SUMO抑制延长了DNMT1陷入DNA的时间，从而导致DNA损伤。在与TAK981和5-Aza-2'联合处理的细胞中观察到DNA损伤的增加。这两种药物在 vitro 中协同减少了B细胞淋巴瘤系列的细胞增殖，包括伯基特淋巴瘤和DLBCL。在 vivo 实验中，结合TAK981（25mg/kg）和5-Aza-2'（2.5mg/kg）在正位异种移植模型中显示了明显的伯基特淋巴瘤的生长抑制。我们的结果表明，根据分子机制的洞察力量身定制药物组合的潜力，以提高癌症治疗的效果。 © 2023年作者（们）。

Combination therapies targeting malignancies aim to increase treatment efficacy and reduce toxicity. Hypomethylating drug 5-Aza-2'-deoxycytidine (5-Aza-2') enhances transcription of tumor suppressor genes and induces replication errors via entrapment of DNMT1, yielding DNA-protein crosslinks. Post-translational modification by SUMO plays major roles in the DNA damage response and is required for degradation of entrapped DNMT1. Here, we combine SUMOylation inhibitor TAK981 and DNA-hypomethylating agent 5-Aza-2'-deoxycytidine to improve treatment of MYC driven hematopoietic malignancies, since MYC overexpressing tumors are sensitive to SUMOylation inhibition. We studied the classical MYC driven malignancy Burkitt lymphoma, as well as diffuse large B-cell lymphoma (DLBCL) with and without MYC translocation. SUMO inhibition prolonged the entrapment of DNMT1 to DNA, resulting in DNA damage. An increase in DNA damage was observed in cells co-treated with TAK981 and 5-Aza-2'. Both drugs synergized to reduce cell proliferation in vitro in a B cell lymphoma cell panel, including Burkitt lymphoma and DLBCL. In vivo experiments combining TAK981 (25 mg/kg) and 5-Aza-2' (2.5 mg/kg) showed a significant reduction in outgrowth of Burkitt lymphoma in an orthotopic xenograft model. Our results demonstrate the potential of tailored combination of drugs, based on insight in molecular mechanisms, to improve the efficacy of cancer therapies.© 2023. The Author(s).