Back to Search
Start Over
Allosteric AKT Inhibitors Target Synthetic Lethal Vulnerabilities in E-Cadherin-Deficient Cells
- Source :
- Cancers, Cancers, Vol 11, Iss 9, p 1359 (2019), Volume 11, Issue 9
- Publication Year :
- 2019
-
Abstract
- The CDH1 gene, encoding the cell adhesion protein E-cadherin, is one of the most frequently mutated genes in gastric cancer and inactivating germline CDH1 mutations are responsible for hereditary diffuse gastric cancer syndrome (HDGC). Using cell viability assays, we identified that breast (MCF10A) and gastric (NCI-N87) cells lacking CDH1 expression are more sensitive to allosteric AKT inhibitors than their CDH1-expressing isogenic counterparts. Apoptosis priming and total apoptosis assays in the isogenic MCF10A cells confirmed the enhanced sensitivity of E-cadherin-null cells to the AKT inhibitors. In addition, two of these inhibitors, ARQ-092 and MK2206, preferentially targeted mouse-derived gastric Cdh1&minus<br />/&minus<br />organoids for growth arrest. AKT protein expression and activation (as measured by phosphorylation of serine 473) were differentially regulated in E-cadherin-null MCF10A and NCI-N87 cells, with downregulation in the normal breast cells, but upregulation in the gastric cancer cells. Bioinformatic analysis of the TCGA STAD dataset revealed that AKT3, but not AKT1 or AKT2, is upregulated in the majority of E-cadherin-deficient gastric cancers. In conclusion, allosteric AKT inhibitors represent a promising class of drugs for chemoprevention and chemotherapy of cancers with E-cadherin loss.
- Subjects :
- 0301 basic medicine
Cancer Research
AKT1
AKT2
lcsh:RC254-282
AKT3
Article
CDH1
03 medical and health sciences
0302 clinical medicine
Downregulation and upregulation
medicine
diffuse gastric cancer
chemoprevention
Protein kinase B
biology
Chemistry
AKT
E-cadherin
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
medicine.disease
synthetic lethality
030104 developmental biology
Oncology
030220 oncology & carcinogenesis
Cancer cell
Cancer research
biology.protein
Hereditary diffuse gastric cancer
Subjects
Details
- ISSN :
- 20726694
- Volume :
- 11
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- Cancers
- Accession number :
- edsair.doi.dedup.....8ccd15738194ea5d4753bad0f018c589