Lipreri da Silva Jean Carlos, Lima Keli, Ede Benjamin, Lazarini Mariana, Vicari Hugo Passos, Nogueira Frederico Lisboa, Clayton Natasha S, Pinnell Katy, Silva Wellington Fernandes da, Velloso Elvira Deolinda Rodrigues Pereira, Bendit Israel, Costa-Lotufo Leticia Veras, Rego Eduardo Magalhães, Ridley Anne J, Machado-Neto João Agostinho
Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
Laboratory of Medical Investigation in Pathogenesis and Targeted Therapy in Onco-Immuno-Hematology (LIM-31), Division of Hematology, Hemotherapy and Cell Therapy, Medical School Clinic Hospital, University of São Paulo, São Paulo, Brazil.
Eur J Pharmacol. 2025 Jan 15;987:177161. doi: 10.1016/j.ejphar.2024.177161. Epub 2024 Nov 29.
Ezrin (EZR) is an actin-associated protein that is often upregulated in cancers. Here we investigate the role of EZR in acute lymphoblastic leukemia (ALL) and explore the therapeutic potential of a pharmacological EZR inhibitor, NSC305787. ALL patient cohorts exhibit significantly elevated EZR mRNA levels, indicating its association with the malignant phenotype. Notably, EZR expression does not impact survival outcomes or relevant clinical-laboratory characteristics, suggesting a role in disease initiation rather than therapy response. NSC305787 induces a dose-dependent reduction in ALL cell viability, and is more potent than a related EZR inhibitor, NSC668394. NSC305787 has multiple effects on ALL cells, including apoptosis induction, clonal growth reduction, and inhibition of cell cycle progression. Importantly, it diminishes adhesiveness and invasiveness in ALL cells. Proteomics analysis highlights changes in translation, RNA catabolism, and cell cycle regulation, emphasizing the broad impact of EZR inhibition on ALL cell biology. Ex vivo assays with primary cells from acute myeloid leukemia (AML) and ALL patients demonstrate NSC305787's efficacy across a molecularly heterogeneous group, independent of risk stratification or recurrent mutations. Notably, NSC305787 shows heightened potency in ALL cells, suggesting its potential as a targeted therapy. In conclusion, our results report high EZR expression in adult ALL patients and support NSC305787 as a promising targeted therapy for ALL that should be further explored.
埃兹蛋白（EZR）是一种与肌动蛋白相关的蛋白质，在癌症中常上调。在此，我们研究EZR在急性淋巴细胞白血病（ALL）中的作用，并探索一种药理学EZR抑制剂NSC305787的治疗潜力。ALL患者队列显示EZR mRNA水平显著升高，表明其与恶性表型相关。值得注意的是，EZR表达不影响生存结果或相关临床实验室特征，提示其在疾病起始而非治疗反应中起作用。NSC305787诱导ALL细胞活力呈剂量依赖性降低，且比相关的EZR抑制剂NSC668394更有效。NSC305787对ALL细胞有多种作用，包括诱导凋亡、减少克隆生长和抑制细胞周期进程。重要的是，它降低了ALL细胞的黏附性和侵袭性。蛋白质组学分析突出了翻译、RNA分解代谢和细胞周期调控的变化，强调了EZR抑制对ALL细胞生物学的广泛影响。对急性髓系白血病（AML）和ALL患者原代细胞的体外试验表明，NSC305787在分子异质性群体中均有效，与风险分层或复发突变无关。值得注意的是，NSC305787在ALL细胞中显示出更高的效力，表明其作为靶向治疗的潜力。总之，我们的结果报告了成年ALL患者中EZR的高表达，并支持NSC305787作为一种有前景的ALL靶向治疗药物，值得进一步探索。
