Synthetic Lethal Screens Identify Vulnerabilities in GPCR Signaling and Cytoskeletal Organization in E-Cadherin-Deficient Cells

Molecular Cancer Therapeutics
Bryony J TelfordParry Guilford

Abstract

The CDH1 gene, which encodes the cell-to-cell adhesion protein E-cadherin, is frequently mutated in lobular breast cancer (LBC) and diffuse gastric cancer (DGC). However, because E-cadherin is a tumor suppressor protein and lost from the cancer cell, it is not a conventional drug target. To overcome this, we have taken a synthetic lethal approach to determine whether the loss of E-cadherin creates druggable vulnerabilities. We first conducted a genome-wide siRNA screen of isogenic MCF10A cells with and without CDH1 expression. Gene ontology analysis demonstrated that G-protein-coupled receptor (GPCR) signaling proteins were highly enriched among the synthetic lethal candidates. Diverse families of cytoskeletal proteins were also frequently represented. These broad classes of E-cadherin synthetic lethal hits were validated using both lentiviral-mediated shRNA knockdown and specific antagonists, including the JAK inhibitor LY2784544, Pertussis toxin, and the aurora kinase inhibitors alisertib and danusertib. Next, we conducted a 4,057 known drug screen and time course studies on the CDH1 isogenic MCF10A cell lines and identified additional drug classes with linkages to GPCR signaling and cytoskeletal function that showed evidence...Continue Reading

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Citations

May 29, 2016·Pathology, Research and Practice·Matthias ChristgenHans Kreipe
Dec 3, 2016·Nucleic Acids Research·Yanli WangJian Zhang
Sep 19, 2015·Journal of Biomolecular Screening·Andrew SingleAugustine Chen
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Feb 25, 2019·Archives of Toxicology·Christine WenzCornelia Dietrich
Dec 8, 2020·ELife·Chue Vin ChinJulia A Horsfield
Feb 23, 2021·EMBO Molecular Medicine·George SflomosCathrin Brisken

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