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

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Abstract

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.

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Availability of data and material

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors acknowledge all the research participants contributing to The Cancer Genome Atlas (TCGA) resource for providing high-quality data for analysis.

Funding

This study was supported by grant #2019/23864–7, #2019/25421–5, #2020/12909–7, and #2020/12748–3 from the São Paulo Research Foundation (FAPESP). This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES)—Finance Code 001.

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Author notes

  1. Jean Carlos Lipreri da Silva and Maria Fernanda Lopes Carvalho contributed equally to the study

Authors and Affiliations

  1. Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil

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

  2. Laboratory of Medical Investigation in Pathogenesis and Targeted Therapy in Onco-Immuno-Hematology (LIM-31), Department of Hematology, Faculty of Medicine, University of São Paulo, São Paulo, Brazil

    Keli Lima

Authors
  1. Jean Carlos Lipreri da Silva
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  2. Maria Fernanda Lopes Carvalho
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  3. Livia Bassani Lins de Miranda
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  4. Bruna Oliveira de Almeida
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  5. Keli Lima
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  6. João Agostinho Machado-Neto
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Contributions

Execution of experiments, data analysis and interpretation, and manuscript writing and editing [J.C.L.S., M.F.L.C., L.B.L.M., B.O.A., K.L.]. Conceptualization, formal analysis, supervision, manuscript writing and editing [J.A.M.-N]. All authors reviewed and approved the submitted manuscript.

Corresponding author

Correspondence to João Agostinho Machado-Neto.

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Lipreri da Silva, J.C., Carvalho, M.F.L., de Miranda, L.B.L. et al. NSC305787, a pharmacological ezrin inhibitor, exhibits antineoplastic activity in pancreatic cancer cells. Invest New Drugs 40, 728–737 (2022). https://doi.org/10.1007/s10637-022-01249-z

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  • DOI: https://doi.org/10.1007/s10637-022-01249-z

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