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Contains fulltext : 225261.pdf (Publisher’s version ) (Closed access) 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. To redress the balance between the accessibility, cost, and acceptance of genetic testing and the increased identification of pathogenic variant carriers, the HDGC genetic testing criteria have been relaxed, mainly through less restrictive age limits. Prophylactic total gastrectomy remains the recommended option for gastric cancer risk management in pathogenic CDH1 variant carriers. However, there is increasing confidence from the IGCLC that endoscopic surveillance in expert centres can be safely offered to patients who wish to postpone surgery, or to those whose risk of developing gastric cancer is not well defined.

Simple Summary Germline loss of the CDH1 gene is the primary genetic basis for hereditary diffuse gastric cancer, a disease resulting in elevated risk of both diffuse gastric cancer and lobular breast cancer. Current preventative treatment consists of prophylactic total gastrectomy, a therapy with several associated long-term morbidities. To address the lack of targeted molecular therapies for hereditary diffuse gastric cancer, we have utilized a synthetic lethal approach to identify candidate compounds that can specifically kill CDH1-null cells. Inhibitors of sphingolipid metabolism and vesicle trafficking pathways were identified as promising candidate compounds in a cell line model of CDH1 loss, then further validated in murine-derived organoid models of hereditary diffuse gastric cancer. With further research, these findings may lead to the development of novel chemoprevention strategies for the treatment of hereditary diffuse gastric cancer. Abstract Germline inactivating variants of CDH1 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 CDH1-null cells. We have previously observed that CDH1-null MCF10A cells exhibit a reduced rate of endocytosis relative to wildtype MCF10A cells. To determine whether this deficiency is associated with wider vulnerabilities in vesicle trafficking, we screened isogenic MCF10A cell lines with known inhibitors of autophagy, endocytosis, and sphingolipid metabolism. Relative to wildtype MCF10A cells, CDH1−/− MCF10A cells showed significantly greater sensitivity to several drugs targeting these processes, including the autophagy inhibitor chloroquine, the endocytosis inhibitors chlorpromazine and PP1, and the sphingosine kinase 1 inhibitor PF-543. Synthetic lethality was confirmed in both gastric and mammary organoid models of CDH1 loss, derived from CD44-Cre/Cdh1fl/fl/tdTomato mice. Collectively, these results suggest that both sphingolipid metabolism and vesicle trafficking represent previously unrecognised druggable vulnerabilities in CDH1-null cells and may lead to the development of new therapies for HDGC.

Toll-like receptors (TLRs) are evolutionarily conserved molecules that specifically recognize common microbial patterns, and have a critical role in innate and adaptive immunity. Although TLRs are highly expressed by innate immune cells, particularly antigen-presenting cells, the very first report of a human TLR also described its expression and function within T-cells. Gene knock-out models and adoptive cell transfer studies have since confirmed that TLRs function as important costimulatory and regulatory molecules within T-cells themselves. By acting directly on T-cells, TLR agonists can enhance cytokine production by activated T-cells, increase T-cell sensitivity to T-cell receptor stimulation, promote long-lived T-cell memory, and reduce the suppressive activity of regulatory T-cells. Direct stimulation of T-cell intrinsic TLRs may be a relevant mechanism of action of TLR ligands currently under clinical investigation as cancer immunotherapies. Finally, chimeric antigen receptor (CAR) T-cells afford a new opportunity to specifically exploit T-cell intrinsic TLR function. This can be achieved by expressing TLR signaling domains, or domains from their signaling partner myeloid differentiation primary response 88 (MyD88), within or alongside the CAR. This review summarizes the expression and function of TLRs within T-cells, and explores the relevance of T-cell intrinsic TLR expression to the benefits and risks of TLR-stimulating cancer immunotherapies, including CAR T-cells.

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, /&minus, 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.