Transcriptomic profiling and quantitative high-throughput (qHTS) drug screening of CDH1 deficient hereditary diffuse gastric cancer (HDGC) cells identify treatment leads for familial gastric cancer

Journal of Translational Medicine

Research

Sarangan Ravichandran¹  Lesley Mathews-Greiner²  Marc Ferrer²  Xiaohu Zhang²  Craig Thomas²  Raj Guha²  Berkley Gryder³  Joal D. Beane⁴  Satyajit Ray⁵  Athina Zacharia⁶  Udo Rudloff⁶  Yansong Bian⁶  Vivek Shukla⁶  Dandan Li⁶  Abisola Abisoye-Ogunniyan⁷  Ina Chen⁸ 

[1] Advanced Biomedical Computing Center, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD, USA;Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA;Genetics Branch, NCI, NIH, Bethesda, MD, USA;Indiana University School of Medicine, Indianapolis, IN, USA;Surgery Branch, NCI, NIH, Bethesda, MD, USA;Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, National Institutes for Health, CCR 4 West/4-3740, 10 Center Drive, 20892-0001, Bethesda, MD, USA;Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, National Institutes for Health, CCR 4 West/4-3740, 10 Center Drive, 20892-0001, Bethesda, MD, USA;Department of Biology and Center for Cancer Research, Tuskegee University, Tuskegee, AL, USA;Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, National Institutes for Health, CCR 4 West/4-3740, 10 Center Drive, 20892-0001, Bethesda, MD, USA;Washington University School of Medicine, St. Louis, KY, USA;

关键词: Hereditary diffuse gastric cancer (HDGC);    High throughput drug screening;    Therapeutic leads;    c.1380delA CDH1 gastric cancer cells;    Differential gene expression profiling;   

DOI  :  10.1186/s12967-017-1197-5

 received in 2017-02-02, accepted in 2017-04-24,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundPatients with hereditary diffuse gastric cancer (HDGC), a cancer predisposition syndrome associated with germline mutations of the CDH1 (E-cadherin) gene, have few effective treatment options. Despite marked differences in natural history, histopathology, and genetic profile to patients afflicted by sporadic gastric cancer, patients with HDGC receive, in large, identical systemic regimens. The lack of a robust preclinical in vitro system suitable for effective drug screening has been one of the obstacles to date which has hampered therapeutic advances in this rare disease.MethodsIn order to identify therapeutic leads selective for the HDGC subtype of gastric cancer, we compared gene expression profiles and drug phenotype derived from an oncology library of 1912 compounds between gastric cancer cells established from a patient with metastatic HDGC harboring a c.1380delA CDH1 germline variant and sporadic gastric cancer cells.ResultsUnsupervised hierarchical cluster analysis shows select gene expression alterations in c.1380delA CDH1 SB.mhdgc-1 cells compared to a panel of sporadic gastric cancer cell lines with enrichment of ERK1–ERK2 (extracellular signal regulated kinase) and IP3 (inositol trisphosphate)/DAG (diacylglycerol) signaling as the top networks in c.1380delA SB.mhdgc-1 cells. Intracellular phosphatidylinositol intermediaries were increased upon direct measure in c.1380delA CDH1 SB.mhdgc-1 cells. Differential high-throughput drug screening of c.1380delA CDH1 SB.mhdgc-1 versus sporadic gastric cancer cells identified several compound classes with enriched activity in c.1380 CDH1 SB.mhdgc-1 cells including mTOR (Mammalian Target Of Rapamycin), MEK (Mitogen-Activated Protein Kinase), c-Src kinase, FAK (Focal Adhesion Kinase), PKC (Protein Kinase C), or TOPO2 (Topoisomerase II) inhibitors. Upon additional drug response testing, dual PI3K (Phosphatidylinositol 3-Kinase)/mTOR and topoisomerase 2A inhibitors displayed up to >100-fold increased activity in hereditary c.1380delA CDH1 gastric cancer cells inducing apoptosis most effectively in cells with deficient CDH1 function.ConclusionIntegrated pharmacological and transcriptomic profiling of hereditary diffuse gastric cancer cells with a loss-of-function c.1380delA CDH1 mutation implies various pharmacological vulnerabilities selective to CDH1-deficient familial gastric cancer cells and suggests novel treatment leads for future preclinical and clinical treatment studies of familial gastric cancer.

【 授权许可】

CC BY   
© The Author(s) 2017