A STAT3 DEGRADER DEMONSTRATES PRE-CLINICAL EFFICACY IN VENETOCLAX RESISTANT MDS & AML

IF 0.7 Q4 HEMATOLOGY Leukemia Research Reports Pub Date : 2024-01-01 DOI:10.1016/j.lrr.2024.100445
A. Shastri, S. Chakraborty, C. Morganti, H. Zhang, B. Rivera-Pena, K. Ito, M. Konopleva
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Abstract

Introduction

High-risk MDS & AML are the result of malignant transformation of an immature hematopoietic precursor. Venetoclax (Ven) is a selective inhibitor of the anti-apoptotic BCL2 protein that is FDA approved for the treatment of AML, despite which, the overall cure rates in HR-MDS and AML are dismal. Signal transducer and activator of transcription 3 (STAT3) is de-methylation and overexpression in MDS & AML stem cells. It is associated with an adverse prognosis in a large cohort of patients. We have also demonstrated that STAT3 controls several important leukemic drivers such as the anti-apoptotic protein MCL1, which is the central mechanism of venetoclax resistance.

Methods

Ven resistant AML cell lines (MOLM-13, MV-4-11) demonstrated an increased expression of STAT3/ Phospho-STAT3 and the down-stream effector MCL1 when compared to parental cell lines. Data from > 90 AML patients treated with prior venetoclax show that high expression of STAT3 correlated with worse overall survival and remission duration.

Results

A clinical degrader of STAT3 resulted in degradation of STAT3 in both parental and ven resistant cancer cell lines. STAT3 degradation also resulted in increased apoptosis in parental & Ven resistant MOLM-13 cell line. In primary patient colony assays, there was increased erythroid and myeloid differentiation on treatment with a STAT3 degrader. Furthermore, murine model of venetoclax resistance showed significant reduction in STAT3 & MCL1 on treatment with the STAT3 degrader.

Conclusions

Targeting STAT3 and downstream MCL1 is novel strategy in MDS/AML that can spur clinical development of the STAT3 degraders especially given the significant side profile of direct MCL1 inhibitors.

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一种Stat3降解剂显示出对耐药MDS和AML的临床前疗效
导言高危骨髓增生异常综合征(MDS)和急性髓细胞性白血病(AML)是未成熟造血前体恶性转化的结果。Venetoclax(Ven)是一种抗凋亡BCL2蛋白的选择性抑制剂,已被FDA批准用于治疗急性髓细胞性白血病,尽管如此,HR-MDS和急性髓细胞性白血病的总体治愈率仍然令人沮丧。信号转导和激活转录 3(STAT3)在 MDS 和 AML 干细胞中存在去甲基化和过表达现象。它与大量患者的不良预后有关。我们还证明,STAT3 控制着几种重要的白血病驱动因子,如抗凋亡蛋白 MCL1,而这正是 Venetoclax 耐药的核心机制。方法与亲代细胞系相比,Ven 耐药的 AML 细胞系(MOLM-13、MV-4-11)显示出 STAT3/磷酸化 STAT3 和下行效应因子 MCL1 的表达增加。结果 STAT3的一种临床降解剂导致STAT3在亲代细胞系和对Venetoclax耐药的癌细胞系中降解。STAT3降解还导致亲代和对Ven耐药的MOLM-13细胞系的细胞凋亡增加。在原发性患者集落试验中,使用 STAT3 降解剂处理后,红细胞和骨髓分化增加。结论靶向 STAT3 和下游 MCL1 是治疗 MDS/AML 的新策略,可以促进 STAT3 降解剂的临床开发,特别是考虑到直接 MCL1 抑制剂的副作用很大。
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来源期刊
Leukemia Research Reports
Leukemia Research Reports Medicine-Oncology
CiteScore
1.70
自引率
0.00%
发文量
70
审稿时长
23 weeks
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