Passenger gene coamplifications create collateral therapeutic vulnerabilities in cancer Journal Article
| Authors: | Bei, Y.; Bramé, L.; Kirchner, M.; Fritsche-Guenther, R.; Kunz, S.; Bhattacharya, A.; Rusu, M. C.; Gürgen, D.; Dubios, F. P. B.; Köppke, J. K. C.; Proba, J.; Wittstruck, N.; Sidorova, O. A.; González, R. C.; Garcia, H. D.; Brückner, L.; Xu, R.; Giurgiu, M.; Rodriguez-Fos, E.; Yu, Q.; Spanjaard, B.; Koche, R. P.; Schmitt, C. A.; Schulte, J. H.; Eggert, A.; Haase, K.; Kirwan, J.; Hagemann, A. I. H.; Mertins, P.; Dörr, J. R.; Henssen, A. G. |
| Article Title: | Passenger gene coamplifications create collateral therapeutic vulnerabilities in cancer |
| Abstract: | DNA amplifications in cancer do not only harbor oncogenes. We sought to determine whether passenger coamplifications could create collateral therapeutic vulnerabili-ties. 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 coam-plification 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. © 2024 The Authors; Published by the American Association for Cancer Research. |
| Keywords: | signal transduction; controlled study; human cell; genetics; neoplasm; neoplasms; quality control; electron microscopy; cell death; cell viability; gene amplification; gene expression; tumor volume; oncology; oncogenes; in situ hybridization; oncogene; genetic transfection; western blotting; immunoprecipitation; immunoblotting; medical oncology; high performance liquid chromatography; protein structure; mass fragmentography; clonogenic assay; oxygen consumption; mtor signaling; metabolomics; mammalian target of rapamycin complex 1; liquid chromatography-mass spectrometry; tricarboxylic acid; humans; human; article; rna sequencing; ic50; crispr cas system; coimmunoprecipitation; mtt assay; malignant neoplasm; oxygen consumption rate; hek293t cell line; mechanistic target of rapamycin complex 1 |
| Journal Title: | Cancer Discovery |
| Volume: | 14 |
| Issue: | 3 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2024-03-01 |
| Start Page: | 492 |
| End Page: | 507 |
| Language: | English |
| DOI: | 10.1158/2159-8290.Cd-23-1189 |
| PUBMED: | 38197697 |
| PROVIDER: | scopus |
| PMCID: | PMC10911929 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
