Kinase Inhibitor Screening Displayed ALK as a Possible Therapeutic Biomarker for Gastric Cancer

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  • Mesquita, Felipe Pantoja
    • Other Affiliation: Federal University of Ceará
  • Souza, Pedro Filho Noronha
    • Other Affiliation: Federal University of Ceará
  • da Silva, Emerson Lucena
    • Other Affiliation: Federal University of Ceará
  • Lima, Luina Benevides
    • Other Affiliation: Federal University of Ceará
  • de Oliveira, Lais Lacerda Brasil
    • Other Affiliation: Federal University of Ceará
  • Moreira-Nunes, Caroline Aquino
    • Other Affiliation: Federal University of Ceará
  • Zuercher, William J.
    • Affiliation: Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry
  • Burbano, Rommel Mario Rodríguez
    • Other Affiliation: Federal University of Pará
  • de Moraes, Maria Elisabete Amaral
    • Other Affiliation: Federal University of Ceará
  • Montenegro, Raquel Carvalho
    • Other Affiliation: Federal University of Ceará
Abstract
  • Despite advances in cancer chemotherapy, gastric cancer (GC) continues to have high recurrence rates and poor prognosis with limited treatment options. Understanding the etiology of GC and developing more effective, less harmful therapeutic approaches are vital and urgent. Therefore, this work describes a novel kinase target in malignant gastric cells as a potential therapeutic strategy. Our results demonstrate that among 147 kinase inhibitors (KI), only three molecules were significantly cytotoxic for the AGP-01 cell line. Hence, these three molecules were further characterized in their cellular mode of action. There was significant cell cycle impairment due to the expression modulation of genes such as TP53, CDKN1A, CDC25A, MYC, and CDK2 with subsequent induction of apoptosis. In fact, the Gene Ontology analysis revealed a significant enrichment of pathways related to cell cycle regulation (GO:1902749 and GO:1903047). Moreover, the three selected KIs significantly reduced cell migration and Vimentin mRNA expression after treatment. Surprisingly, the three KIs share the same target, ALK and INSR, but only the ALK gene was found to have a high expression level in the gastric cancer cell line. Additionally, lower survival rates were observed for patients with high ALK expression in TCGA-STAD analysis. In summary, we hypothesize that ALK gene overexpression can be a promising biomarker for prognosis and therapeutic management of gastric adenocarcinoma.
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  • Article
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  • In Copyright
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  • Attribution 4.0 International
Journal title
  • Pharmaceutics
Journal volume
  • 14
Journal issue
  • 9
Page start
  • 1841
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  • English
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  • Publisher
ISSN
  • 1999-4923

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