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.

E-Cadherin-Deficient Epithelial Cells Are Sensitive to HDAC Inhibitors.

Inactivating germline mutations in the gene (encoding the E-cadherin protein) are the genetic hallmark of hereditary diffuse gastric cancer (HDGC), and somatic mutations are an early event in the development of sporadic diffuse gastric cancer (DGC) and lobular breast cancer (LBC). In this study, histone deacetylase (HDAC) inhibitors were tested for their ability to preferentially inhibit the growth of human cell lines (MCF10A and NCI-N87) and murine organoids lacking expression. breast and gastric cells were more sensitive to the pan-HDAC inhibitors entinostat, pracinostat, mocetinostat and vorinostat than wild-type cells, with an elevated growth inhibition that was, in part, attributable to increased apoptosis.

Loss of E-Cadherin Leads to Druggable Vulnerabilities in Sphingolipid Metabolism and Vesicle Trafficking.

Germline inactivating variants of are causative of hereditary diffuse gastric cancer (HDGC), a cancer syndrome characterized by an increased risk of both diffuse gastric cancer and lobular breast cancer. Because loss of function mutations are difficult to target therapeutically, we have taken a synthetic lethal approach to identify targetable vulnerabilities in -null cells. We have previously observed that -null MCF10A cells exhibit a reduced rate of endocytosis relative to wildtype MCF10A cells.

Discovery of AL-GDa62 as a Potential Synthetic Lethal Lead for the Treatment of Gastric Cancer.

Diffuse gastric cancer and lobular breast cancer are aggressive malignancies that are frequently associated with inactivating mutations in the tumor suppressor gene Synthetic lethal (SL) vulnerabilities arising from dysfunction represent attractive targets for drug development. Recently, SLEC-11 () emerged as a SL lead in E-cadherin-deficient cells. Here, we describe our efforts to optimize .

Hereditary diffuse gastric cancer: updated clinical practice guidelines.

Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome that is characterised by a high prevalence of diffuse gastric cancer and lobular breast cancer. It is largely caused by inactivating germline mutations in the tumour suppressor gene CDH1, although pathogenic variants in CTNNA1 occur in a minority of families with HDGC. In this Policy Review, we present updated clinical practice guidelines for HDGC from the International Gastric Cancer Linkage Consortium (IGCLC), which recognise the emerging evidence of variability in gastric cancer risk between families with HDGC, the growing capability of endoscopic and histological surveillance in HDGC, and increased experience of managing long-term sequelae of total gastrectomy in young patients.

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

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 hereditary diffuse gastric cancer syndrome (HDGC). Using cell viability assays, we identified that breast (MCF10A) and gastric (NCI-N87) cells lacking expression are more sensitive to allosteric AKT inhibitors than their -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.

PI3K Catalytic Subunits α and β Modulate Cell Death and IL-6 Secretion Induced by Talc Particles in Human Lung Carcinoma Cells.

Hydrated magnesium silicate (or "talc" particles) is a sclerosis agent commonly used in the management of malignant pleural effusions, a common symptom of metastatic diseases, including lung cancers. However, the direct effects of talc particles to lung carcinoma cells, which can be found in the malignant pleural effusion fluids from patients with lung cancer, are not fully understood. Here, we report a study of the signaling pathways that can modulate the cell death and IL-6 secretion induced by talc particles in human lung carcinoma cells.

E-cadherin-deficient cells have synthetic lethal vulnerabilities in plasma membrane organisation, dynamics and function.

Background: The E-cadherin gene (CDH1) is frequently mutated in diffuse gastric cancer and lobular breast cancer, and germline mutations predispose to the cancer syndrome Hereditary Diffuse Gastric Cancer. We are taking a synthetic lethal approach to identify druggable vulnerabilities in CDH1-mutant cancers.

Methods: Density distributions of cell viability data from a genome-wide RNAi screen of isogenic MCF10A and MCF10A-CDH1 cells were used to identify protein classes affected by CDH1 mutation.

Early spatiotemporal-specific changes in intermediate signals are predictive of cytotoxic sensitivity to TNFα and co-treatments.

Signaling pathways can generate different cellular responses to the same cytotoxic agents. Current quantitative models for predicting these differential responses are usually based on large numbers of intracellular gene products or signals at different levels of signaling cascades. Here, we report a study to predict cellular sensitivity to tumor necrosis factor alpha (TNFα) using high-throughput cellular imaging and machine-learning methods.

Large-scale image-based screening and profiling of cellular phenotypes.

Cellular phenotypes are observable characteristics of cells resulting from the interactions of intrinsic and extrinsic chemical or biochemical factors. Image-based phenotypic screens under large numbers of basal or perturbed conditions can be used to study the influences of these factors on cellular phenotypes. Hundreds to thousands of phenotypic descriptors can also be quantified from the images of cells under each of these experimental conditions.