title: MEDICI: Mining Essentiality Data to Identify Critical Interactions for Cancer Drug Target Discovery and Development.
abstract: Protein-protein interactions (PPIs) mediate the transmission and regulation of oncogenic signals that are essential to cellular proliferation and survival, and thus represent potential targets for anti-cancer therapeutic discovery. Despite their significance, there is no method to experimentally disrupt and interrogate the essentiality of individual endogenous PPIs. The ability to computationally predict or infer PPI essentiality would help prioritize PPIs for drug discovery and help advance understanding of cancer biology. Here we introduce a computational method (MEDICI) to predict PPI essentiality by combining gene knockdown studies with network models of protein interaction pathways in an analytic framework. Our method uses network topology to model how gene silencing can disrupt PPIs, relating the unknown essentialities of individual PPIs to experimentally observed protein essentialities. This model is then deconvolved to recover the unknown essentialities of individual PPIs. We demonstrate the validity of our approach via prediction of sensitivities to compounds based on PPI essentiality and differences in essentiality based on genetic mutations. We further show that lung cancer patients have improved overall survival when specific PPIs are no longer present, suggesting that these PPIs may be potentially new targets for therapeutic development. Software is freely available at https://github.com/cooperlab/MEDICI. Datasets are available at https://ctd2.nci.nih.gov/dataPortal.
authors.affiliation: Department of Biomedical Informatics, Emory University, Atlanta, Georgia, United States of America.|Graduate Program in Biomedical Informatics, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Sahar
authors.initials: S
authors.lastname: Harati
authors.affiliation: Department of Biomedical Informatics, Emory University, Atlanta, Georgia, United States of America.|Winship Cancer Institute, Emory University, Atlanta, Georgia, United States of America.|Department of Biomedical Engineering, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Lee A D
authors.initials: LA
authors.lastname: Cooper
authors.affiliation: Graduate Program in Cancer Biology, Emory University, Atlanta, Georgia, United States of America.|Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Josue D
authors.initials: JD
authors.lastname: Moran
authors.affiliation: Medical Scientist Training Program, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Felipe O
authors.initials: FO
authors.lastname: Giuste
authors.affiliation: Winship Cancer Institute, Emory University, Atlanta, Georgia, United States of America.|Department of Pharmacology, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Pharmacology, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Andrei A
authors.initials: AA
authors.lastname: Ivanov
authors.affiliation: Department of Pharmacology, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Johns
authors.affiliation: Winship Cancer Institute, Emory University, Atlanta, Georgia, United States of America.|Department of Hematology & Medical Oncology, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
authors.affiliation: Winship Cancer Institute, Emory University, Atlanta, Georgia, United States of America.|Department of Pharmacology, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Haian
authors.initials: H
authors.lastname: Fu
authors.affiliation: Department of Biomedical Informatics, Emory University, Atlanta, Georgia, United States of America.|Winship Cancer Institute, Emory University, Atlanta, Georgia, United States of America.|Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Carlos S
authors.identifier: http://orcid.org/0000-0002-5582-0028
authors.initials: CS
authors.lastname: Moreno
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000401:mortality; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000401:mortality; D016000:Cluster Analysis; D057225:Data Mining / Q000379:methods*; D055808:Drug Discovery; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000401:mortality; D058990:Molecular Targeted Therapy; D009154:Mutation; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016571:Neural Networks, Computer; D025941:Protein Interaction Mapping; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D012984:Software
chemical_list: D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering