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

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−/− 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.

Modelling hereditary diffuse gastric cancer initiation using transgenic mouse‐derived gastric organoids and single‐cell sequencing

“…All animal experiments were reviewed and approved by the University of Otago Animal Ethics Committee (AUP‐18‐226). Gastric organoids were generated from CD44 ‐Cre/ Cdh1 loxP/loxP / tdTomato mice as described previously [10,11]. In brief, organoids were generated from minced stomach tissue obtained from postnatal day 1 (D1) mice using an air–liquid interface and myofibroblast co‐culture.…”

Molecular target: pan-AKT in gastric cancer

“…Interestingly, Bougen-Zhukov et al observed that AKT3 was upregulated in the majority of E-cadherin-deficient GCs, and mouse-derived gastric organoids lacking tumour suppressor gene CDH1 were sensitive to the apoptotic effects of miransertib. 82 This identification may be useful for providing new therapeutic strategies for hereditary and sporadic GC with mutations in the CDH1 gene, since germline truncation mutations in the CDH1 gene are found in 30%-50% families with hereditary diffuse GC. 83 Clinical perspective: resistance, toxicity and biomarkers The PI3K/AKT/mTOR pathway comprises a complex network of crosstalk with many parallel cascades, so its inhibition induces negative feedback resulting in activation of other compensatory signalling pathways.…”

“…Interestingly, Bougen-Zhukov et al observed that AKT3 was upregulated in the majority of E-cadherin-deficient GCs, and mouse-derived gastric organoids lacking tumour suppressor gene CDH1 were sensitive to the apoptotic effects of miransertib. 82 This identification may be useful for providing new therapeutic strategies for hereditary and sporadic GC with mutations in the CDH1 gene, since germline truncation mutations in the CDH1 gene are found in 30%–50% families with hereditary diffuse GC. 83 …”

Overview on new progress of hereditary diffuse gastric cancer with CDH1 variants

“…Li et al 21 reviewed and further supported promising molecular-targeted treatments with PI3K/mTOR inhibitors for patients with HDGC. Bougen-Zhukov et al 109 found that low levels of E-cadherin made breast (MCF10A) and gastric (NCI-N87) cancer cells more sensitive to allosteric AKT inhibitors than their isogenic wild-type counterparts. Two inhibitors preferentially inhibited the formation of gastric CDH1−/− organoids in mouse models, suggesting a survival benefit for patients with HDGC with CDH1 alterations.…”

“…Two inhibitors preferentially inhibited the formation of gastric CDH1−/− organoids in mouse models, suggesting a survival benefit for patients with HDGC with CDH1 alterations. 109 A new analysis by Beetham et al 110 identified novel synthetic lethal compounds as a new treatment or chemoprevention for E-cadherin-deficient cells via high-throughput screening. This new strategy confers an alternative preponderance on therapy that surpasses the current traditional drugs because it only targets defects in tumors with specific variants, not normal cells.…”