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Allosteric AKT Inhibitors Target Synthetic Lethal Vulnerabilities in E-Cadherin-Deficient Cells

Nicola Bougen-Zhukov1, Yasmin Nouri2, Tanis Godwin3

  • 1Cancer Genetics Laboratory, Centre for Translational Cancer Research (Te Aho Matatū), Department of Biochemistry, University of Otago, Dunedin 9016, New Zealand. nicola.bougen-zhukov@otago.ac.nz.

Cancers
|September 22, 2019
PubMed

Insights

E-cadherin loss in cancer increases sensitivity to AKT inhibitors. These drugs show promise for treating gastric cancer and hereditary diffuse gastric cancer syndrome (HDGC).

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • The CDH1 gene encodes E-cadherin, a cell adhesion protein crucial in preventing cancer.
  • Germline CDH1 mutations cause hereditary diffuse gastric cancer syndrome (HDGC).
  • E-cadherin loss is common in gastric cancers, impacting cell adhesion and potentially treatment response.

Purpose of the Study:

  • To investigate the effect of E-cadherin loss on cancer cell sensitivity to allosteric AKT inhibitors.
  • To explore the therapeutic potential of AKT inhibitors in cancers with CDH1 deficiency.

Main Methods:

  • Cell viability assays were performed on E-cadherin-expressing and E-cadherin-null breast (MCF10A) and gastric (NCI-N87) cancer cells.
  • Apoptosis assays were conducted to confirm sensitivity in isogenic cell lines.
  • Mouse-derived gastric Cdh1-/- organoids were treated with AKT inhibitors.
  • Bioinformatic analysis of the TCGA STAD dataset was used to examine AKT gene expression in E-cadherin-deficient gastric cancers.

Main Results:

  • E-cadherin-null cells exhibited increased sensitivity to allosteric AKT inhibitors compared to E-cadherin-expressing cells.
  • Specific AKT inhibitors (ARQ-092, MK2206) induced growth arrest in mouse gastric Cdh1-/- organoids.
  • AKT protein expression and activation were differentially regulated in E-cadherin-null cells.
  • AKT3 was found to be upregulated in E-cadherin-deficient gastric cancers within the TCGA STAD dataset.

Conclusions:

  • Allosteric AKT inhibitors demonstrate significant efficacy against E-cadherin-deficient cancer cells and organoids.
  • AKT inhibitors represent a potential therapeutic strategy for cancers characterized by E-cadherin loss.
  • Targeting AKT signaling could be beneficial for chemoprevention and chemotherapy in HDGC and other E-cadherin-deficient malignancies.
Keywords:
AKTE-cadherinchemopreventiondiffuse gastric cancersynthetic lethality

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