Skip NavigationSkip to Content

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.

  1. Author:
    Chen, Ina
    Mathews-Greiner, Lesley
    Li, Dandan
    Abisoye-Ogunniyan, Abisola [ORCID]
    Ray, Satyajit
    Bian, Yansong
    Shukla, Vivek
    Zhang, Xiaohu
    Guha, Raj
    Thomas, Craig
    Gryder, Berkley
    Zacharia, Athina
    Beane, Joal D
    Ravichandran, Sarangan
    Ferrer, Marc
    Rudloff, Udo
  2. Author Address

    Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, National Institutes for Health, CCR 4 West/4-3740, 10 Center Drive, Bethesda, MD, 20892-0001, USA., Washington University School of Medicine, St. Louis, KY, USA., Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA., Department of Biology and Center for Cancer Research, Tuskegee University, Tuskegee, AL, USA., Surgery Branch, NCI, NIH, Bethesda, MD, USA., Genetics Branch, NCI, NIH, Bethesda, MD, USA., Indiana University School of Medicine, Indianapolis, IN, USA., Advanced Biomedical Computing Center, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD, USA., Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, National Institutes for Health, CCR 4 West/4-3740, 10 Center Drive, Bethesda, MD, 20892-0001, USA. rudloffu@mail.nih.gov.,
    1. Year: 2017
    2. Date: May 01
    3. Epub Date: 2017 May 01
  1. Journal: Journal of translational medicine
    1. 15
    2. 1
    3. Pages: 92
  2. Type of Article: Article
  3. Article Number: 92
  4. ISSN: 1479-5876
  1. Abstract:

    Patients 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. In 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. Unsupervised 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. Integrated 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.

    See More

External Sources

  1. DOI: 10.1186/s12967-017-1197-5
  2. PMID: 28460635
  3. PMCID: PMC5412046
  4. WOS: 000400611300006

Library Notes

  1. Fiscal Year: FY2016-2017
NCI at Frederick

You are leaving a government website.

This external link provides additional information that is consistent with the intended purpose of this site. The government cannot attest to the accuracy of a non-federal site.

Linking to a non-federal site does not constitute an endorsement by this institution or any of its employees of the sponsors or the information and products presented on the site. You will be subject to the destination site's privacy policy when you follow the link.

ContinueCancel