PO.ET02.13 · 实验与分子治疗
协同靶向Mediator复合物和BCL-2揭示急性髓系白血病的新型治疗策略
Synergistic targeting of Mediator complex and BCL-2 reveals a novel therapeutic strategy for acute myeloid leukemia
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：急性髓系白血病（AML）是一种异质性强、侵袭性高的血液系统恶性肿瘤，其特征为髓系干细胞和祖细胞的不受控增殖。尽管治疗手段有所进步，5年生存率仍然很低，凸显出对新型治疗策略的迫切需求。
方法：为满足这一需求并鉴定新的抗白血病药物，我们使用56种具有不同遗传异常的原代AML标本，对10,000种小分子进行了高通量细胞活力筛选。将呈现高度相关抑制谱的分子归入21个化合物相关性簇（CCCs）。总体假设是共享高度相关抑制谱的化合物最有可能作用于同一生物学通路/分子靶点。在所鉴定的各个CCC中，包含化合物AML874的CCC163脱颖而出，成为一个强效且选择性的抗白血病命中化合物。
结果：整合的药理学和CRISPR-Cas9筛选揭示Mediator复合物是AML874的分子靶点。机制研究证实，AML874通过抑制CDK8/CDK19激酶来抑制Mediator复合物的功能，导致转录失调和Mediator结构完整性的丧失。激酶失活的CDK8挽救实验证实AML874的活性依赖于CDK8的激酶功能。值得注意的是，FLT3突变的AML原代标本对AML874表现出更高的敏感性，提示存在潜在的亚型特异性治疗机会。AML874类似物的构效关系分析进一步支持了抗白血病活性对Mediator复合物破坏的依赖性。最后，联合研究表明AML874与BCL2抑制剂venetoclax在体外和体内均具有强协同作用，在异种移植模型中显著提升了抗白血病活性。
结论：这项工作确定Mediator复合物是AML中一个新的易感靶点，并将CDK8/CDK19抑制（单独或与Venetoclax联合）定位为开发该疾病下一代靶向疗法的一种有前景策略。
查看英文原文 English abstract
Background: Acute myeloid leukemia (AML) is a heterogeneous and aggressive hematologic malignancy characterized by the uncontrolled proliferation of myeloid stem and progenitor cells. Despite therapeutic advances, the 5-year survival rate remains low, underscoring the urgent need for novel therapeutic strategies.
Methods: To meet this need and identify new anti-leukemic agents, we conducted a high-throughput cell viability screen of 10,000 small molecules using 56 different primary AML specimens of diverse genetic anomalies. Molecules showing highly correlated inhibition profiles were grouped into 21 compound correlation clusters (CCCs). The overall hypothesis was that compounds sharing highly correlated inhibition profiles most likely act on the same biological pathway / molecular target. Among the various CCC identified, CCC163, which include compound AML874, emerged as a potent and selective anti-leukemic hit.
Results: Integrated pharmacological and CRISPR-Cas9 screening revealed the Mediator complex as the molecular target of AML874. Mechanistic studies confirmed that AML874 inhibits Mediator complex function through CDK8/CDK19 kinase inhibition, leading to transcriptional dysregulation and loss of Mediator structural integrity. Kinase-dead CDK8 rescue assays confirmed that AML874 activity depends on CDK8 kinase function. Notably, FLT3-mutated AML primary specimens exhibited increased sensitivity to AML874, indicating a potential subtype-specific therapeutic opportunity. Structure-activity relationship profiling of AML874 analogs further supported the dependency on Mediator complex disruption for anti-leukemic activity. Finally, combination studies demonstrated strong synergy between AML874 and the BCL2 inhibitor venetoclax both in vitro and in vivo, resulting in markedly improved anti-leukemic activity in xenograft models.
Conclusions: This work identifies the Mediator complex as a novel vulnerability in AML and positions CDK8/CDK19 inhibition, alone or in combination with Venetoclax, as a promising strategy for the development of next-generation targeted therapies for this disease.
利益披露 Disclosure
C. Aitchedji, None..
C. Moison, None..
D. Gracias, None..
R. Mendoza-Sanchez, None..
S. Fortier, None..
J. Spinella, None..
T. Macrae, None..
N. Mayotte, None..
M. Frechette, None..
V. Blouin-Chagnon, None..
K. Leveillé, None..
R. Ruel, None..
A. Marinier, None..
G. Sauvageau, None..
J. Hébert, None.