Article ; Online: Network-based elucidation of colon cancer drug resistance mechanisms by phosphoproteomic time-series analysis.
2024 Volume 15, Issue 1, Page(s) 3909
Abstract: Aberrant signaling pathway activity is a hallmark of tumorigenesis and progression, which has guided targeted inhibitor design for over 30 years. Yet, adaptive resistance mechanisms, induced by rapid, context-specific signaling network rewiring, continue ...
Abstract | Aberrant signaling pathway activity is a hallmark of tumorigenesis and progression, which has guided targeted inhibitor design for over 30 years. Yet, adaptive resistance mechanisms, induced by rapid, context-specific signaling network rewiring, continue to challenge therapeutic efficacy. Leveraging progress in proteomic technologies and network-based methodologies, we introduce Virtual Enrichment-based Signaling Protein-activity Analysis (VESPA)-an algorithm designed to elucidate mechanisms of cell response and adaptation to drug perturbations-and use it to analyze 7-point phosphoproteomic time series from colorectal cancer cells treated with clinically-relevant inhibitors and control media. Interrogating tumor-specific enzyme/substrate interactions accurately infers kinase and phosphatase activity, based on their substrate phosphorylation state, effectively accounting for signal crosstalk and sparse phosphoproteome coverage. The analysis elucidates time-dependent signaling pathway response to each drug perturbation and, more importantly, cell adaptive response and rewiring, experimentally confirmed by CRISPR knock-out assays, suggesting broad applicability to cancer and other diseases. |
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MeSH term(s) | Humans ; Drug Resistance, Neoplasm/genetics ; Drug Resistance, Neoplasm/drug effects ; Proteomics/methods ; Phosphoproteins/metabolism ; Signal Transduction/drug effects ; Colonic Neoplasms/drug therapy ; Colonic Neoplasms/metabolism ; Colonic Neoplasms/genetics ; Cell Line, Tumor ; Phosphorylation ; Algorithms ; Proteome/metabolism ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use |
Chemical Substances | Phosphoproteins ; Proteome ; Antineoplastic Agents |
Language | English |
Publishing date | 2024-05-09 |
Publishing country | England |
Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't |
ZDB-ID | 2553671-0 |
ISSN | 2041-1723 ; 2041-1723 |
ISSN (online) | 2041-1723 |
ISSN | 2041-1723 |
DOI | 10.1038/s41467-024-47957-3 |
Database | MEDical Literature Analysis and Retrieval System OnLINE |
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