Therapeutic targeting of SIRT3 for aggressive and refractory lymphomas

摘要 在侵袭性淋巴瘤中，弥漫大B细胞淋巴瘤(DLBCL)是 大多数高度增殖，并对新陈代谢前体的生产有大量需求。 沿着这些路线，我们最近发现了NAD+依赖的赖氨酸脱乙酰基酶SIRT3，它是一种主酶 线粒体应激代谢调节因子作为DLBCL生长和生长的关键驱动因素 生死存亡。我们发现，DLBCL细胞中SIRT3功能的丧失通过破坏 他们在TCA循环中使用谷氨酰胺和其他氨基酸的能力，这会引发破坏性的 自噬--体外和体内都是如此。重要的是，我们创造了以SIRT3为靶点的线粒体 选择性小分子YC8-02，精确模拟SIRT3耗竭和有效 体外和体内对DLBCL细胞的杀伤作用。这些化合物产生了进一步增强的杀灭效果。 结合靶向治疗，如万乃馨以及化疗药物 通常用于治疗DLBCL。最后，我们的机械数据指向了细胞中 可能最终导致对SIRT3靶向治疗的耐药性，以及防止这种情况的方法 避免发生，从而产生最大的治疗效果。最大的挑战是 为DLBCL患者提供精确药物是他们显著的遗传异质性和 极其丰富的体细胞突变。目前没有具有活动的目标代理 以及与一小部分患者相关的目标。然而，我们发现了SIRT3 作为广泛相关和严重的非癌基因成瘾，是DLBCL所必需的 与他们的遗传背景无关。通过这项建议，我们为i)提供了基础 将SIRT3抑制剂转化为临床，II)了解和缓解潜在的耐药性 机制，以及iii)将SIRT3抑制剂纳入合理设计的抗淋巴瘤 对迫切需要改善的患者亚群具有广泛相关性的方案 治疗。我们的建议使用最先进的模型系统在生理上与这些 复杂的肿瘤，并准备从科学和临床上带来极具影响力的结果 透视。

ABSTRACT Among aggressive lymphomas, the Diffuse large B-cell lymphomas (DLBCLs) are among the most highly proliferative, and have massive requirements for production of metabolic precursors. Along these lines we recently identified NAD+ dependent lysine deacetylase SIRT3, as a master regulator of mitochondrial stress metabolism, as a critical driver of DLBCL growth and survival. We showed that SIRT3 loss of function in DLBCL cells kills lymphomas by disrupting their ability to use glutamine and other amino acids in the TCA cycle, which triggers destructive autophagy – both in vitro and in vivo. Importantly, we created the mitochondrial targeted SIRT3 selective small molecule YC8-02 that precisely mimics the effect of SIRT3 depletion and potently killed DLBCL cells in vitro and in vivo. These compounds yielded further enhanced killing effects in combination with targeted therapies such as venetoclax as well with chemotherapy drugs commonly used to treat DLBCLs. Finally, our mechanistic data point to pathways in cells that could eventually lead to resistance to SIRT3 targeted therapy, as well as ways to prevent this from happening so as to yield maximal therapeutic efficacy. An overarching challenge in delivering precision medicine for DLBCL patients is their marked genetic heterogeneity and extreme abundance of somatic mutations. There are currently no targeted agents with activity and targets relevant to more than a small fraction of patients. However, we identified SIRT3 as a broadly relevant and critical non-oncogene addiction that is required by DLBCLs independent of their genetic background. Through this proposal we provide the basis for i) translating SIRT3 inhibitors to the clinic, ii) understanding and mitigating potential resistance mechanisms, and iii) incorporating SIRT3 inhibitors into rationally designed anti-lymphoma regimens with broad relevance for the subsets of patients who desperately need improved therapies. Our proposal uses state of the art model systems physiologically relevant to these complex tumors, and is poised to deliver highly impactful outcomes from the scientific and clinical perspective.