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Passenger gene co-amplifications create collateral therapeutic vulnerabilities in cancer

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Item Type:Article
Title:Passenger gene co-amplifications create collateral therapeutic vulnerabilities in cancer
Creators Name:Bei, Y. and Brame, Luca and Kirchner, M. and Fritsche-Guenther, R. and Kunz, S. and Bhattacharya, A. and Rusu, M.C. and Gürgen, D. and Dubois, F.P.B. and Köppke, J.K.C. and Proba, J. and Wittstruck, N. and Sidorova, O.A. and Chamorro González, R. and Dorado Garcia, H. and Brückner, L. and Xu, R. and Giurgiu, M. and Rodriguez-Fos, E. and Yu, Q. and Spanjaard, B. and Koche, R.P, and Schmitt, C.A. and Schulte, J.H. and Eggert, A. and Haase, K. and Kirwan, J. and Hagemann, A.I. and Mertins, P. and Dörr, J.R. and Henssen, A.G.
Abstract:DNA amplifications in cancer do not only harbor oncogenes. We sought to determine whether passenger co-amplifications 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 co-amplifications are accompanied by distinct dependency profiles. In a proof-of-principle study, we demonstrate that co-amplification of the bona fide passenger gene DEAD-Box Helicase 1 (DDX1) creates an increased dependency to 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 co-amplification of a passenger gene and an oncogene can result in collateral vulnerabilities. SIGNIFICANCE: 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.
Keywords:Animals, Mice, Zebrafish
Source:Cancer Discovery
ISSN:2159-8274
Publisher:American Association for Cancer Research
Date:13 January 2024
Official Publication:https://doi.org/10.1158/2159-8290.CD-23-1189
PubMed:View item in PubMed

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