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

The gene, encoding the cell adhesion protein E-cadherin, is one of the most frequently mutated genes in gastric cancer and inactivating germline mutations are responsible for the cancer syndrome hereditary diffuse gastric cancer (HDGC). -deficient gastric cancers exhibit high AKT serine/threonine kinase 3 ( expression, but specific drugs against this AKT isoform are not available. We therefore used two publicly available datasets to identify -associated genes which could be used to indirectly target AKT3. Reactome analysis identified an enrichment of extracellular matrix remodelling genes in -high gastric cancers. Of the 51 genes that were significantly correlated with (but not ), discoidin domain receptor tyrosine kinase 2 () showed the strongest positive association. Treatment of isogenic human cells and mouse gastric and mammary organoids with dasatinib, a small molecule inhibitor of multiple kinases including SRC, BCR-ABL and DDR2, preferentially slowed the growth and induced apoptosis of E-cadherin-deficient cells. Dasatinib treatment also preferentially slowed the growth of gastric and mammary organoids harbouring both and mutations. In organoid models, dasatinib treatment was associated with decreased phosphorylation of total AKT, with a stronger effect seen in -deficient organoids. Treatment with combinations of dasatinib and an inhibitor of AKT, MK2206, enhanced the effect of dasatinib in breast MCF10A cells. In conclusion, targeting the DDR2-SRC-AKT3 axis with dasatinib represents a promising approach for the chemoprevention and chemotherapy of gastric and breast cancers lacking E-cadherin.