ONC213: a novel strategy to resensitize resistant AML cells to venetoclax through induction of mitochondrial stress.

IF 12.8 1区医学 Q1 ONCOLOGY Journal of Experimental & Clinical Cancer Research Pub Date : 2025-01-09 DOI:10.1186/s13046-024-03267-6

Jenna L Carter, Yongwei Su, Eman T Al-Antary, Jianlei Zhao, Xinan Qiao, Guan Wang, Holly Edwards, Lisa Polin, Juiwanna Kushner, Sijana H Dzinic, Kathryn White, Steven A Buck, Maik Hüttemann, Joshua E Allen, Varun V Prabhu, Jay Yang, Jeffrey W Taub, Yubin Ge

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Abstract

Background: Venetoclax + azacitidine is a frontline treatment for older adult acute myeloid leukemia (AML) patients and a salvage therapy for relapsed/refractory patients who have been treated with intensive chemotherapy. While this is an important treatment option, many patients fail to achieve complete remission and of those that do, majority relapse. Leukemia stem cells (LSCs) are believed to be responsible for AML relapse and can be targeted through oxidative phosphorylation reduction. We previously reported that ONC213 disrupts oxidative phosphorylation and decreases Mcl-1 protein, which play a key role in venetoclax resistance. Here we investigated the antileukemic activity and underlying molecular mechanism of the combination of ONC213 + venetoclax against AML cells.

Methods: Flow cytometry was used to determine drug-induced apoptosis. Protein level changes were determined by western blot. An AML cell line-derived xenograft mouse model was used to determine the effects of ONC213 + venetoclax on survival. A patient-derived xenograft (PDX) mouse model was used to determine drug effects on CD45+/CD34+/CD38-/CD123 + cells. Colony formation assays were used to assess drug effects on AML progenitor cells. Mcl-1 and Bax/Bak knockdown and Mcl-1 overexpression were used to confirm their role in the mechanism of action. The effect of ONC213 + venetoclax on mitochondrial respiration was determined using a Seahorse bioanalyzer.

Results: ONC213 + venetoclax synergistically kills AML cells, including those resistant to venetoclax alone as well as venetoclax + azacitidine. The combination significantly reduced colony formation capacity of primary AML progenitors compared to the control and either treatment alone. Further, the combination prolonged survival in an AML cell line-derived xenograft model and significantly decreased LSCs in an AML PDX model.

Conclusions: ONC213 can resensitize VEN + AZA-resistant AML cells to venetoclax therapy and target LSCs ex vivo and in vivo.

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ONC213：一种通过诱导线粒体应激使耐药AML细胞对venetoclax重新敏感的新策略

背景：Venetoclax +阿扎胞苷是老年成人急性髓性白血病（AML）患者的一线治疗药物，也是已接受强化化疗的复发/难治性患者的救助治疗药物。虽然这是一种重要的治疗选择，但许多患者未能完全缓解，而那些完全缓解的患者中，大多数复发。白血病干细胞（LSCs）被认为是AML复发的原因，并且可以通过氧化磷酸化还原来靶向。我们之前报道了ONC213破坏氧化磷酸化并降低Mcl-1蛋白，这在venetoclax抗性中起关键作用。在这里，我们研究了ONC213 + venetoclax联合抗AML细胞的抗白血病活性和潜在的分子机制。方法：采用流式细胞术检测药物诱导的细胞凋亡。western blot检测蛋白水平变化。使用AML细胞系来源的异种移植小鼠模型来确定ONC213 + venetoclax对生存的影响。采用患者源性异种移植（PDX）小鼠模型来确定药物对CD45+/CD34+/CD38-/CD123 +细胞的影响。采用菌落形成法评估药物对AML祖细胞的影响。用Mcl-1和Bax/Bak敲低和Mcl-1过表达来证实其作用机制。采用海马生物分析仪测定ONC213 + venetoclax对线粒体呼吸的影响。结果：ONC213 + venetoclax协同杀死AML细胞，包括对venetoclax单独耐药以及venetoclax +阿扎胞苷耐药的细胞。与对照组和单独治疗相比，联合治疗显著降低了原发性AML祖细胞的集落形成能力。此外，该组合延长了AML细胞系来源的异种移植模型中的存活时间，并显著减少了AML PDX模型中的LSCs。结论：ONC213可以使VEN + aza耐药的AML细胞对venetoclax治疗重新敏感，并在体内和体外靶向LSCs。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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索莱宝

JC-1

来源期刊

Journal of Experimental & Clinical Cancer Research 医学-肿瘤学

CiteScore

18.20

自引率

1.80%

发文量

333

审稿时长

1 months

期刊介绍： The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.