PO.ET02.10 · 实验与分子治疗

临床级CK2抑制剂CX-4945在临床前急性髓系白血病模型中协同增强venetoclax介导的抗白血病活性

Clinical-grade CK2 inhibitor CX-4945 synergistically enhances venetoclax-mediated antileukemic activity in preclinical acute myeloid leukemia models

编号 4466 展板 14 时间 4/21 09:00–12:00 区域 Section 13 主讲 Upendar Golla, PhD

分会场 Drug Combinations, Repurposing, and Differentiation

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作者与单位 Authors & Affiliations

Upendarrao Golla, Muhammad Danial, Rajesh Rajaiah, Marudhu Pandiyan Shanmugam, Koby Duke, Katherine Mercer, Yi Qiu, Sinisa Dovat, Yasin Uzun, Hong Zheng, Suming Huang, Chandrika G. Behura

Penn State College of Medicine, Hershey, PA

摘要 Abstract

中文摘要

引言：凋亡机制和信号传导失调是急性髓系白血病（AML）对含venetoclax（VEN，一种BCL2（B细胞淋巴瘤-2）抑制剂）方案获得性耐药的原因，构成临床挑战。酪蛋白激酶2（CK2）是一种丝氨酸/苏氨酸激酶，拥有300多种底物，调节细胞周期、存活、分化和凋亡。其异常活性促进疾病进展、不良预后和耐药。CX-4945（CX）是一种选择性CK2抑制剂，在白血病和其他实体瘤中显示出强效抗癌活性。在此，我们在临床前AML模型中检验了用CX和VEN联合靶向CK2和BCL2。方法：在AML细胞系和原代样本中通过WST和annexin V实验检验CX+VEN联合的细胞毒和促凋亡效应。使用SynergyFinder工具确定ZIP协同评分。流式细胞术和免疫印迹评估药物处理后的细胞表面标志物、多种凋亡调节因子以及CK2靶点水平。动态BH3谱分析评估CX处理后VEN耐药（VR）细胞对凋亡的启动。通过RNA测序分析处理与未处理的VR-AML细胞的转录组。在细胞系和患者来源异种移植（PDX）小鼠模型中检验CX+VEN联合的体内疗效。结果：在BeatAML队列中，CK2alpha（CSNK2A1）表达与VEN活性呈负相关，类似于BCL2水平，且VR-AML细胞显示出更高的CK2活性。CX+VEN联合在VEN敏感（MOLM13、HL60、THP1）、VR-AML（U937、MOLM13/VR、HL60/VR）细胞系和PDX细胞体外显示出协同细胞毒性并增强凋亡。CX处理增强了VR-AML细胞对BH3肽的启动并增加细胞色素c释放。此外，CX+VEN联合有效诱导凋亡并减少VR-AML细胞中的白血病干细胞（CD34+CD38-）和化疗耐药（CD47+CD123+）亚群。CX+VEN联合处理后，AML细胞显示CK2活性和其他促存活BCL2家族成员蛋白下调，PARP活性增加。CX+VEN联合处理后转录组的功能富集分析显示，在VR-AML细胞中被抑制的细胞周期停滞、TP53和凋亡特征基因上调。最后，CX+VEN联合在体内有效减少了异种移植（CDX/PDX）小鼠的白血病负荷并延长了总体中位生存期。结论：CX+VEN联合在不同的临床前AML模型中显示出优越的抗白血病活性，且CK2抑制克服了VEN耐药。CX-4945（Silmitasertib）具有良好的药代动力学和良好的人体耐受性，正在早期临床试验阶段进行评估。我们的发现为CK2和BCL2共靶向作为AML治疗和克服VEN耐药的有效方法提供了理论依据。

查看英文原文 English abstract

Introduction: Dysregulated apoptotic machinery and signaling contribute to acquire resistance to regimens containing venetoclax (VEN), a BCL2 (B-cell lymphoma-2) inhibitor, in acute myeloid leukemia (AML) and pose a clinical challenge. Casein kinase 2 (CK2) is a serine/threonine kinase with 300+ substrates and regulate cell cycle, survival, differentiation, and apoptosis. Its aberrant activity promotes disease progression, poor prognosis, and drug resistance. CX-4945 (CX), a selective CK2 inhibitor, shows potent anticancer activity in leukemia and other solid tumors. Here, we tested combined CK2 and BCL2 targeting with CX and VEN in pre-clinical AML models. Methods: Cytotoxic and pro-apoptotic effects of the CX+VEN combo were tested in AML cell lines and primary samples by WST and annexin V assays. The ZIP synergy score was determined by SynergyFinder tool. Flow cytometry and immunoblotting assessed cell surface markers, various apoptosis regulators along with CK2 target levels after drug treatment. Dynamic BH3 profiling assessed priming of VEN-resistant (VR) cells to apoptosis after CX treatment. Transcriptome of VR-AML cells with and without drug treatment was analyzed by RNA sequencing. In vivo efficacy of CX+VEN combo was tested in cell line and patient-derived xenograft (PDX) mouse models. Results: CK2alpha ( CSNK2A1 ) expression exhibited negative correlation similar to that of BCL2 levels with VEN activity in BeatAML cohort and VR-AML cells showed higher CK2 activity. CX+VEN combo showed synergistic cytotoxicity and augmented apoptosis in VEN-sensitive (MOLM13, HL60, THP1), VR-AML (U937, MOLM13/VR, HL60/VR) cell lines, and PDX cells in vitro . CX treatment enhanced VR-AML cells priming to BH3 peptides and increased cytochrome c release. Also, CX+VEN combo effectively induced apoptosis and decreased leukemia stem cells (CD34+CD38-) and chemo-resistant (CD47+CD123+) subpopulations in VR-AML cells. AML cells showed downregulation of CK2 activity and other pro-survival BCL2 member family proteins with increased PARP activity after CX+VEN combo treatment. Functional enrichment analysis of transcriptome after CX+VEN combo treatment showed upregulation of cell cycle arrest, TP53 and apoptotic signature genes that were repressed in VR-AML cells. Lastly, CX+VEN combo effectively decreased leukemia burden and prolonged overall median survival of xenograft (CDX/PDX) mice in vivo . Conclusions: CX+VEN combo showed a superior antileukemic activity in different pre-clinical AML models and CK2 inhibition overcome VEN resistance. CX-4945 (Silmitasertib) has favorable pharmacokinetics with good tolerability in human studies and is being evaluated in early phases of clinical trial. Our findings provide a rationale for CK2 and BCL2 co-targeting as an effective approach for AML treatment and to overcome VEN resistance.

利益披露 Disclosure

U. Golla, None.. M. Danial, None.. R. Rajaiah, None.. M. Shanmugam, None.. K. Duke, None.. K. Mercer, None.. Y. Qiu, None.. S. Dovat, None.. Y. Uzun, None.. H. Zheng, None.. S. Huang, None.. C. G. Behura, None.

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