Title
Genome-wide prediction of synthetic rescue mediators of resistance to targeted and immunotherapy
UMMS Affiliation
Program in Systems Biology
Publication Date
2019-03-11
Document Type
Article
Disciplines
Immunology and Infectious Disease | Immunoprophylaxis and Therapy | Molecular Biology | Systems Biology | Therapeutics
Abstract
Most patients with advanced cancer eventually acquire resistance to targeted therapies, spurring extensive efforts to identify molecular events mediating therapy resistance. Many of these events involve synthetic rescue (SR) interactions, where the reduction in cancer cell viability caused by targeted gene inactivation is rescued by an adaptive alteration of another gene (the rescuer). Here, we perform a genome-wide in silico prediction of SR rescuer genes by analyzing tumor transcriptomics and survival data of 10,000 TCGA cancer patients. Predicted SR interactions are validated in new experimental screens. We show that SR interactions can successfully predict cancer patients' response and emerging resistance. Inhibiting predicted rescuer genes sensitizes resistant cancer cells to therapies synergistically, providing initial leads for developing combinatorial approaches to overcome resistance proactively. Finally, we show that the SR analysis of melanoma patients successfully identifies known mediators of resistance to immunotherapy and predicts novel rescuers.
Keywords
drug combination, drug resistance, immunotherapy, synergy
Rights and Permissions
Copyright 2019 The Authors. Published under the terms of the CC BY 4.0 license. License: This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
DOI of Published Version
10.15252/msb.20188323
Source
Mol Syst Biol. 2019 Mar 11;15(3):e8323. doi: 10.15252/msb.20188323. Link to article on publisher's site
Journal/Book/Conference Title
Molecular systems biology
Related Resources
PubMed ID
30858180
Repository Citation
Sahu, Avinash Das; Ponomarova, Olga; and Ruppin, Eytan, "Genome-wide prediction of synthetic rescue mediators of resistance to targeted and immunotherapy" (2019). Open Access Articles. 3804.
https://escholarship.umassmed.edu/oapubs/3804
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Included in
Immunoprophylaxis and Therapy Commons, Molecular Biology Commons, Systems Biology Commons, Therapeutics Commons
Comments
Full author list omitted for brevity. For the full list of authors, see article.