ONC213：一种通过诱导线粒体应激使耐药急性髓系白血病细胞对维奈托克重新敏感的新策略。
ONC213: a novel strategy to resensitize resistant AML cells to venetoclax through induction of mitochondrial stress.
作者信息
Carter Jenna L, Su Yongwei, Al-Antary Eman T, Zhao Jianlei, Qiao Xinan, Wang Guan, Edwards Holly, Polin Lisa, Kushner Juiwanna, Dzinic Sijana H, White Kathryn, Buck Steven A, Hüttemann Maik, Allen Joshua E, Prabhu Varun V, Yang Jay, Taub Jeffrey W, Ge Yubin
机构信息
Cancer Biology Graduate Program, Wayne State University School of Medicine, Detroit, MI, 48201, USA.
MD/PhD Program, Wayne State University School of Medicine, Detroit, MI, 48201, USA.
出版信息
J Exp Clin Cancer Res. 2025 Jan 9;44(1):10. doi: 10.1186/s13046-024-03267-6.
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.
背景
维奈托克联合阿扎胞苷是老年急性髓系白血病（AML）患者的一线治疗方案，也是接受过强化化疗的复发/难治性患者的挽救治疗方案。虽然这是一种重要的治疗选择，但许多患者未能实现完全缓解，而实现完全缓解的患者中，大多数会复发。白血病干细胞（LSCs）被认为是AML复发的原因，可通过降低氧化磷酸化来靶向治疗。我们之前报道过ONC213会破坏氧化磷酸化并降低Mcl-1蛋白水平，而Mcl-1蛋白在维奈托克耐药中起关键作用。在此，我们研究了ONC213联合维奈托克对AML细胞的抗白血病活性及潜在分子机制。
方法
采用流式细胞术检测药物诱导的细胞凋亡。通过蛋白质印迹法测定蛋白质水平变化。利用AML细胞系来源的异种移植小鼠模型确定ONC213联合维奈托克对生存期的影响。采用患者来源的异种移植（PDX）小鼠模型确定药物对CD45+/CD34+/CD38-/CD123+细胞的作用。采用集落形成试验评估药物对AML祖细胞的作用。通过敲低Mcl-1和Bax/Bak以及过表达Mcl-1来证实它们在作用机制中的作用。使用海马生物能量分析仪测定ONC213联合维奈托克对线粒体呼吸的影响。
结果
ONC213联合维奈托克可协同杀死AML细胞，包括那些单独对维奈托克耐药以及对维奈托克联合阿扎胞苷耐药的细胞。与对照组及单独使用任一药物相比，该联合用药显著降低了原发性AML祖细胞的集落形成能力。此外，该联合用药延长了AML细胞系来源的异种移植模型的生存期，并显著减少了AML PDX模型中的LSCs。
结论
ONC213可使对维奈托克联合阿扎胞苷耐药的AML细胞对维奈托克治疗重新敏感，并在体外和体内靶向LSCs。
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