Life sciences · 2022
Ezrin is highly expressed and a druggable target in chronic lymphocytic leukemia.
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Lipreri da Silva Jean Carlos, Saldanha-Araujo Felipe, de Melo Raphael Costa Bandeira, Vicari Hugo Passos, Silva-Carvalho Amandda Evelin, Rego Eduardo Magalhães, Buccheri Valeria, Machado-Neto João Agostinho
Аннотация
AIMS: Despite the development of therapeutic strategies for chronic lymphocytic leukemia (CLL), most patients remain incurable, relapse, or refractory to current treatments, indicating the need to expand the antineoplastic repertoire for this disease. Ezrin (EZR) is a known oncogene in solid tumors and plays a key role in cell survival and BCR-mediated signaling activation in B-cell lymphomas. However, its role in hematological neoplasms remains poorly explored.
MAIN METHODS: The present study assessed EZR expression in samples from CLL patients and healthy donors and evaluated the cellular and molecular effects of a pharmacological EZR inhibitor, NSC305787, in CLL cellular models.
KEY FINDINGS: EZR was highly expressed and positively associated with relevant signaling pathways related to CLL development and progression, including TP53, PI3K/AKT/mTOR, NF-κB, and MAPK. NSC305787 reduced viability, clonogenicity, and cell cycle progression and induced apoptosis in CLL cells. Pharmacological EZR inhibition also attenuated ERK, S6RP, and NF-κB activation, indicating that EZR not only associates with but also activates these signaling pathways in CLL. Ex vivo assays revealed that the EZR inhibition-induced cell viability reduction was independent of molecular risk and the Binet stage.
SIGNIFICANCE: Our study provides insights into EZR as a pharmacological target in CLL, shedding light on a novel strategy for treating this disease.
MAIN METHODS: The present study assessed EZR expression in samples from CLL patients and healthy donors and evaluated the cellular and molecular effects of a pharmacological EZR inhibitor, NSC305787, in CLL cellular models.
KEY FINDINGS: EZR was highly expressed and positively associated with relevant signaling pathways related to CLL development and progression, including TP53, PI3K/AKT/mTOR, NF-κB, and MAPK. NSC305787 reduced viability, clonogenicity, and cell cycle progression and induced apoptosis in CLL cells. Pharmacological EZR inhibition also attenuated ERK, S6RP, and NF-κB activation, indicating that EZR not only associates with but also activates these signaling pathways in CLL. Ex vivo assays revealed that the EZR inhibition-induced cell viability reduction was independent of molecular risk and the Binet stage.
SIGNIFICANCE: Our study provides insights into EZR as a pharmacological target in CLL, shedding light on a novel strategy for treating this disease.