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E-Cadherin-Deficient Cells Are Sensitive to the Multikinase Inhibitor Dasatinib.

Nicola Bougen-Zhukov1, Lyvianne Decourtye-Espiard1, Wilson Mitchell1

  • 1Centre for Translational Cancer Research (Te Aho Matatū), Cancer Genetics Laboratory, Department of Biochemistry, University of Otago, Dunedin 9016, New Zealand.

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|April 12, 2022
PubMed
Summary

Targeting the DDR2-SRC-AKT3 pathway with dasatinib shows promise for treating E-cadherin-deficient gastric and breast cancers by slowing tumor growth and inducing apoptosis.

Keywords:
AKT serine/threonine kinase 3 AKT3E-cadherinHDGCchemopreventiondasatinibdiffuse gastric cancerdiscoidin domain receptor 2 (DDR2)lobular breast cancersynthetic lethality

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Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Germline CDH1 mutations cause hereditary diffuse gastric cancer (HDGC).
  • CDH1-deficient gastric cancers show high AKT3 expression, lacking targeted therapies.
  • Identifying AKT3-associated genes can enable indirect therapeutic targeting.

Purpose of the Study:

  • To identify genes associated with AKT3 expression in CDH1-deficient cancers.
  • To evaluate dasatinib as a therapeutic agent targeting the identified pathway.
  • To assess the efficacy of dasatinib in preclinical models of gastric and breast cancer.

Main Methods:

  • Analysis of public datasets to identify AKT3-associated genes.
  • Reactome pathway analysis to identify enriched gene sets.
  • Treatment of human cell lines and organoid models with dasatinib and AKT inhibitors.
  • Assessment of cell growth, apoptosis, and AKT phosphorylation.

Main Results:

  • Discoidin domain receptor tyrosine kinase 2 (DDR2) showed the strongest positive association with AKT3.
  • Dasatinib preferentially inhibited growth and induced apoptosis in E-cadherin-deficient cells and organoids.
  • Combined dasatinib and AKT inhibitor treatment enhanced therapeutic effects in breast cells.

Conclusions:

  • Targeting the DDR2-SRC-AKT3 axis with dasatinib is a potential strategy for E-cadherin-deficient cancers.
  • Dasatinib demonstrates efficacy in preclinical models of gastric and breast cancer.
  • This approach offers a promising avenue for cancer chemoprevention and chemotherapy.