NSC305787, a pharmacological ezrin inhibitor, exhibits antineoplastic activity in pancreatic cancer cells

Autor(es)

Lipreri da Silva, Jean Carlos ; Carvalho, Maria Fernanda Lopes ; de Miranda, Livia Bassani Lins ; de Almeida, Bruna Oliveira ; Lima, Keli ; Machado-Neto, Joao Agostinho

• Tipo de documento: Artigo Científico
• Fonte: INVESTIGATIONAL NEW DRUGS; v. N/A, p. 10-pg., 2022-04-28.

Resumo

Pancreatic cancer is one of the most lethal human neoplasms, and despite advances in the understanding of the molecular complexity involved in the development and progression of this disease, little of this new information has been translated into improvements in therapy and prognosis. Ezrin (EZR) is a protein that regulates multiple cellular functions, including cell proliferation, survival, morphogenesis, adhesion, and motility. In pancreatic cancer, EZR is highly expressed and reflects an unfavorable prognosis, whereas EZR silencing ameliorates the malignant phenotype of pancreatic cancer cells. NSC305787 was identified as a pharmacological EZR inhibitor with favorable pharmacokinetics and antineoplastic activity. Here, we endeavored to investigate the impact of EZR expression on survival outcomes and its associations with molecular and biological characteristics in The Cancer Genome Atlas pancreatic adenocarcinoma cohort. We also assessed the potential antineoplastic effects of NSC305787 in pancreatic cancer cell lines. High EZR expression was an independent predictor of worse survival outcomes. Functional genomics analysis indicated that EZR contributes to multiple cancer-related pathways, including PI3K/AKT/mTOR signaling, NOTCH signaling, estrogen-mediated signaling, and apoptosis. In pancreatic cells, NSC305787 reduced cell viability, clonal growth, and migration. Our exploratory molecular studies identified that NSC305787 modulates the expression and activation of key regulators of the cell cycle, proliferation, DNA damage, and apoptosis, favoring a tumor-suppressive molecular network. In conclusion, EZR expression is an independent prognosis marker in pancreatic cancer. Our study identifies a novel molecular axis underlying the antineoplastic activity of NSC305787 and provides insights into the development of therapeutic strategies for pancreatic cancer. (AU)

• Processo FAPESP: 19/23864-7 - Análise compreensiva de dados genômicos para identificação e validação de novos alvos terapêuticos envolvidos na regulação de citoesqueleto celular em Leucemias agudas
• Beneficiário: João Agostinho Machado Neto
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 20/12909-7 - Investigação do potencial antineoplásico da inibição de ezrina em modelos de Leucemias agudas
• Beneficiário: Jean Carlos Lipreri da Silva
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 20/12748-3 - Investigação dos efeitos de NT157, fármaco com múltiplos alvos anticâncer, em modelos celulares de câncer de pulmão
• Beneficiário: Lívia Bassani Lins de Miranda
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica