Pharmacologically controlling protein-protein interactions through epichaperomes for therapeutic vulnerability in cancer
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Published:2021-11-25
Issue:1
Volume:4
Page:
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ISSN:2399-3642
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Container-title:Communications Biology
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language:en
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Short-container-title:Commun Biol
Author:
Joshi Suhasini, Gomes Erica DaGama, Wang Tai, Corben Adriana, Taldone Tony, Gandu SrinivasaORCID, Xu Chao, Sharma SahilORCID, Buddaseth Salma, Yan PengrongORCID, Chan Lon Yin L., Gokce Askan, Rajasekhar Vinagolu K., Shrestha Lisa, Panchal Palak, Almodovar Justina, Digwal Chander S.ORCID, Rodina AnnaORCID, Merugu Swathi, Pillarsetty NagaVaraKishoreORCID, Miclea VladORCID, Peter Radu I.ORCID, Wang WanyanORCID, Ginsberg Stephen D., Tang Laura, Mattar Marissa, de Stanchina Elisa, Yu Kenneth H., Lowery Maeve, Grbovic-Huezo OliveraORCID, O’Reilly Eileen M.ORCID, Janjigian Yelena, Healey John H.ORCID, Jarnagin William R., Allen Peter J., Sander Chris, Erdjument-Bromage HediyeORCID, Neubert Thomas A., Leach Steven D.ORCID, Chiosis GabrielaORCID
Abstract
AbstractCancer cell plasticity due to the dynamic architecture of interactome networks provides a vexing outlet for therapy evasion. Here, through chemical biology approaches for systems level exploration of protein connectivity changes applied to pancreatic cancer cell lines, patient biospecimens, and cell- and patient-derived xenografts in mice, we demonstrate interactomes can be re-engineered for vulnerability. By manipulating epichaperomes pharmacologically, we control and anticipate how thousands of proteins interact in real-time within tumours. Further, we can essentially force tumours into interactome hyperconnectivity and maximal protein-protein interaction capacity, a state whereby no rebound pathways can be deployed and where alternative signalling is supressed. This approach therefore primes interactomes to enhance vulnerability and improve treatment efficacy, enabling therapeutics with traditionally poor performance to become highly efficacious. These findings provide proof-of-principle for a paradigm to overcome drug resistance through pharmacologic manipulation of proteome-wide protein-protein interaction networks.
Funder
U.S. Department of Health & Human Services | NIH | National Cancer Institute U.S. Department of Health & Human Services | NIH | National Institute on Aging
Publisher
Springer Science and Business Media LLC
Subject
General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology,Medicine (miscellaneous)
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