Perturbation biology links temporal protein changes to drug responses in a melanoma cell line

• DOI: 10.1371/journal.pcbi.1007909
• Publication Date: 2020-07-15T17:47:18Z
• Authors: Elin Nyman; Richard R. Stein; Xiaohong Jing; Weiqing Wang; Benjamin Marks; Ioannis K. Zervan...; Anil Korkut; Nicholas P. Gauthier; Chris Sander
• Keywords: Crosstalk

Cancer cells have genetic alterations that often directly affect intracellular protein signaling processes allowing them to bypass control mechanisms for cell death, growth and division. drugs targeting these work initially, but resistance is common. Combinations of targeted may overcome or prevent resistance, their selection requires context-specific knowledge pathways including complex interactions such as feedback loops crosstalk. To infer quantitative pathway models, we collected a rich dataset on melanoma line: Following perturbation with 54 drug combinations, measured 124 (phospho-)protein levels phenotypic response (cell growth, apoptosis) in time series from 10 minutes 67 hours. From data, trained time-resolved mathematical models capture molecular the coupling cellular phenotype, which turn reveal main direct indirect responses each drug. Systematic model simulations identified novel combinations predicted reduce survival cells, partial experimental verification. This particular application biology demonstrates potential impact combining data modeling discovery new cancer drugs.