Network-based elucidation of colon cancer drug resistance mechanisms by phosphoproteomic time-series analysis

George Rosenberger, Wenxue Li, Mikko Turunen, Jing He, Prem S. Subramaniam, Sergey Pampou, Aaron T. Griffin, Charles Karan, Patrick Kerwin, Diana Murray, Barry Honig, Yansheng Liu () and Andrea Califano ()
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George Rosenberger: Columbia University Irving Medical Center
Wenxue Li: Yale University
Mikko Turunen: Columbia University Irving Medical Center
Jing He: Columbia University Irving Medical Center
Prem S. Subramaniam: Columbia University Irving Medical Center
Sergey Pampou: Columbia University Irving Medical Center
Aaron T. Griffin: Columbia University Irving Medical Center
Charles Karan: Columbia University Irving Medical Center
Patrick Kerwin: Columbia University Irving Medical Center
Diana Murray: Columbia University Irving Medical Center
Barry Honig: Columbia University Irving Medical Center
Yansheng Liu: Yale University
Andrea Califano: Columbia University Irving Medical Center

Nature Communications, 2024, vol. 15, issue 1, 1-27

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-47957-3

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