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Supplementary Table S6 from Passenger Gene Coamplifications Create Collateral Therapeutic Vulnerabilities in Cancer

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posted on 2024-03-01, 12:00 authored by Yi Bei, Luca Bramé, Marieluise Kirchner, Raphaela Fritsche-Guenther, Severine Kunz, Animesh Bhattacharya, Mara-Camelia Rusu, Dennis Gürgen, Frank P.B. Dubios, Julia K.C. Köppke, Jutta Proba, Nadine Wittstruck, Olga Alexandra Sidorova, Rocío Chamorro González, Heathcliff Dorado Garcia, Lotte Brückner, Robin Xu, Mădălina Giurgiu, Elias Rodriguez-Fos, Qinghao Yu, Bastiaan Spanjaard, Richard P. Koche, Clemens A. Schmitt, Johannes H. Schulte, Angelika Eggert, Kerstin Haase, Jennifer Kirwan, Anja I.H. Hagemann, Philipp Mertins, Jan R. Dörr, Anton G. Henssen

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Funding

Deutsche Forschungsgemeinschaft (DFG)

Deutsche Krebshilfe (German Cancer Aid)

Berlin Institute of Health (BIH)

Deutschen Konsortium für Translationale Krebsforschung (DKTK)

European Research Council (ERC)

Cancer Research UK (CRUK)

Wilhelm Sander-Stiftung (Wilhelm Sander Foundation)

History

ARTICLE ABSTRACT

DNA amplifications in cancer do not only harbor oncogenes. We sought to determine whether passenger coamplifications could create collateral therapeutic vulnerabilities. Through an analysis of >3,000 cancer genomes followed by the interrogation of CRISPR-Cas9 loss-of-function screens across >700 cancer cell lines, we determined that passenger coamplifications are accompanied by distinct dependency profiles. In a proof-of-principle study, we demonstrate that the coamplification of the bona fide passenger gene DEAD-Box Helicase 1 (DDX1) creates an increased dependency on the mTOR pathway. Interaction proteomics identified tricarboxylic acid (TCA) cycle components as previously unrecognized DDX1 interaction partners. Live-cell metabolomics highlighted that this interaction could impair TCA activity, which in turn resulted in enhanced mTORC1 activity. Consequently, genetic and pharmacologic disruption of mTORC1 resulted in pronounced cell death in vitro and in vivo. Thus, structurally linked coamplification of a passenger gene and an oncogene can result in collateral vulnerabilities. We demonstrate that coamplification of passenger genes, which were largely neglected in cancer biology in the past, can create distinct cancer dependencies. Because passenger coamplifications are frequent in cancer, this principle has the potential to expand target discovery in oncology.This article is featured in Selected Articles from This Issue, p. 384

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