Large-Scale Characterization of Drug Responses of Clinically Relevant Proteins in Cancer Cell Lines

• Published in: Cancer cell Vol. 38; no. 6; pp. 829 - 843.e4
• Main Authors: Zhao, Wei, Li, Jun, Chen, Mei-Ju M., Luo, Yikai, Ju, Zhenlin, Nesser, Nicole K., Johnson-Camacho, Katie, Boniface, Christopher T., Lawrence, Yancey, Pande, Nupur T., Davies, Michael A., Herlyn, Meenhard, Muranen, Taru, Zervantonakis, Ioannis K., von Euw, Erika, Schultz, Andre, Kumar, Shwetha V., Korkut, Anil, Spellman, Paul T., Akbani, Rehan, Slamon, Dennis J., Gray, Joe W., Brugge, Joan S., Lu, Yiling, Mills, Gordon B., Liang, Han
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.12.2020
• Subjects: Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; biomarker; cancer signaling pathway; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Computational Biology; Drug Resistance, Neoplasm; drug response; Humans; Molecular Targeted Therapy; Neoplasms - drug therapy; Neoplasms - metabolism; protein array; Protein Array Analysis; Protein Interaction Maps - drug effects; Proteomics - methods; User-Computer Interface; drug response; cancer signaling pathway; protein array; biomarker
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2020.10.008

Perturbation biology is a powerful approach to modeling quantitative cellular behaviors and understanding detailed disease mechanisms. However, large-scale protein response resources of cancer cell lines to perturbations are not available, resulting in a critical knowledge gap. Here we generated and compiled perturbed expression profiles of ∼210 clinically relevant proteins in >12,000 cancer cell line samples in response to ∼170 drug compounds using reverse-phase protein arrays. We show that integrating perturbed protein response signals provides mechanistic insights into drug resistance, increases the predictive power for drug sensitivity, and helps identify effective drug combinations. We build a systematic map of “protein-drug” connectivity and develop a user-friendly data portal for community use. Our study provides a rich resource to investigate the behaviors of cancer cells and the dependencies of treatment responses, thereby enabling a broad range of biomedical applications. [Display omitted] •A large collection of cancer cell line protein responses to drug perturbations•Perturbed protein responses greatly increase predictive power for drug sensitivity•A systematic map of protein-drug connectivity was built based on response profiles•A user-friendly, interactive data portal was developed for community use Zhao et al. profile the protein responses of a large collection of cancer cell lines to drug perturbations using the RPPA platform and build a systematic protein-drug connectivity map. The integration of perturbed protein responses provides better prediction of drug sensitivity and insights into drug-resistance mechanisms and combination therapies.