Pharmacological inhibition of ezrin reduces proliferative and invasive phenotype in acute lymphoblastic leukemia cells

Jean Carlos Lipreri da Silva; Keli Lima; Benjamin Ede; Mariana Lazarini; Hugo Passos Vicari; Frederico Lisboa Nogueira; Natasha S Clayton; Katy Pinnell; Wellington Fernandes da Silva; Elvira Deolinda Rodrigues Pereira Velloso; Israel Bendit; Leticia Veras Costa-Lotufo; Eduardo Magalhães Rego; Anne J Ridley; João Agostinho Machado-Neto

doi:10.1016/j.ejphar.2024.177161

Pharmacological inhibition of ezrin reduces proliferative and invasive phenotype in acute lymphoblastic leukemia cells

Eur J Pharmacol. 2024 Nov 29:987:177161. doi: 10.1016/j.ejphar.2024.177161. Online ahead of print.

Authors

Jean Carlos Lipreri da Silva¹, Keli Lima², Benjamin Ede³, Mariana Lazarini⁴, Hugo Passos Vicari¹, Frederico Lisboa Nogueira², Natasha S Clayton³, Katy Pinnell³, Wellington Fernandes da Silva², Elvira Deolinda Rodrigues Pereira Velloso², Israel Bendit², Leticia Veras Costa-Lotufo¹, Eduardo Magalhães Rego², Anne J Ridley³, João Agostinho Machado-Neto⁵

Affiliations

¹ Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
² 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.
³ School of Cellular and Molecular Medicine, Faculty of Health and Life Sciences, University of Bristol, Bristol, United Kingdom.
⁴ Department of Clinical and Experimental Oncology, Federal University of São Paulo, São Paulo, Brazil.
⁵ Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil. Electronic address: jamachadoneto@usp.br.

PMID: 39615869
DOI: 10.1016/j.ejphar.2024.177161

Abstract

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.

Keywords: Acute lymphoblastic leukemia; Cytoskeleton; Ezrin; Rho GTPases.