Illuminating phenotypic drug responses of sarcoma cells to kinase inhibitors by phosphoproteomics

• Published in: Molecular systems biology 2024-01, Vol.20 (1), p.28-55
• Main Authors: Lee, Chien-Yun, The, Matthew, Meng, Chen, Bayer, Florian P, Putzker, Kerstin, Müller, Julian, Streubel, Johanna, Woortman, Julia, Sakhteman, Amirhossein, Resch, Moritz, Schneider, Annika, Wilhelm, Stephanie, Kuster, Bernhard
• Format: Article
• Language: English
• Subjects: Biomedical and Life Sciences; EMBO03; EMBO08; EMBO56; Life Sciences; Systems Biology
• ISSN: 1744-4292; 1744-4292
• DOI: 10.1038/s44320-023-00004-7

Kinase inhibitors (KIs) are important cancer drugs but often feature polypharmacology that is molecularly not understood. This disconnect is particularly apparent in cancer entities such as sarcomas for which the oncogenic drivers are often not clear. To investigate more systematically how the cellular proteotypes of sarcoma cells shape their response to molecularly targeted drugs, we profiled the proteomes and phosphoproteomes of 17 sarcoma cell lines and screened the same against 150 cancer drugs. The resulting 2550 phenotypic profiles revealed distinct drug responses and the cellular activity landscapes derived from deep (phospho)proteomes (9–10,000 proteins and 10–27,000 phosphorylation sites per cell line) enabled several lines of analysis. For instance, connecting the (phospho)proteomic data with drug responses revealed known and novel mechanisms of action (MoAs) of KIs and identified markers of drug sensitivity or resistance. All data is publicly accessible via an interactive web application that enables exploration of this rich molecular resource for a better understanding of active signalling pathways in sarcoma cells, identifying treatment response predictors and revealing novel MoA of clinical KIs. Synopsis Computational integration of the phenotypic response of 17 sarcoma cell lines to 139 kinase inhibitors with the baseline (phospho)proteomes of the same cells reveals oncogenic activity landscapes and drug response markers. A molecular resource of the baseline proteotypes and drug phenotypes of 17 sarcoma cell lines and 139 clinical kinase inhibitors is presented. All data is available for integration and interactive visualisation in ProteomicsDB— https://www.proteomicsdb.org/sarquarium . Activity landscapes of 380 kinases shape the response of sarcoma cells to kinase inhibitors and illuminate mechanisms of action. Systematic association of drug phenotypes and (phospho)proteomes identifies markers of drug sensitivity and resistance. Computational integration of the phenotypic response of 17 sarcoma cell lines to 139 kinase inhibitors with the baseline (phospho)proteomes of the same cells reveals oncogenic activity landscapes and drug response markers.