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Proteome activity landscapes of tumor cell lines determine drug responses.

ABSTRACT: Integrated analysis of genomes, transcriptomes, proteomes and drug responses of cancer cell lines (CCLs) is an emerging approach to uncover molecular mechanisms of drug action. We extend this paradigm to measuring proteome activity landscapes by acquiring and integrating quantitative data for 10,000 proteins and 55,000 phosphorylation sites (p-sites) from 125 CCLs. These data are used to contextualize proteins and p-sites and predict drug sensitivity. For example, we find that Progesterone Receptor (PGR) phosphorylation is associated with sensitivity to drugs modulating estrogen signaling such as Raloxifene. We also demonstrate that Adenylate kinase isoenzyme 1 (AK1) inactivates antimetabolites like Cytarabine. Consequently, high AK1 levels correlate with poor survival of Cytarabine-treated acute myeloid leukemia patients, qualifying AK1 as a patient stratification marker and possibly as a drug target. We provide an interactive web application termed ATLANTiC (http://atlantic.proteomics.wzw.tum.de), which enables the community to explore the thousands of novel functional associations generated by this work.

SUBMITTER: Frejno M

PROVIDER: S-EPMC7371697 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Proteome activity landscapes of tumor cell lines determine drug responses.

Frejno Martin M Meng Chen C Ruprecht Benjamin B Oellerich Thomas T Scheich Sebastian S Kleigrewe Karin K Drecoll Enken E Samaras Patroklos P Hogrebe Alexander A Helm Dominic D Mergner Julia J Zecha Jana J Heinzlmeir Stephanie S Wilhelm Mathias M Dorn Julia J Kvasnicka Hans-Michael HM Serve Hubert H Weichert Wilko W Kuster Bernhard B

Nature communications 20200720 1

Integrated analysis of genomes, transcriptomes, proteomes and drug responses of cancer cell lines (CCLs) is an emerging approach to uncover molecular mechanisms of drug action. We extend this paradigm to measuring proteome activity landscapes by acquiring and integrating quantitative data for 10,000 proteins and 55,000 phosphorylation sites (p-sites) from 125 CCLs. These data are used to contextualize proteins and p-sites and predict drug sensitivity. For example, we find that Progesterone Recep ...[more]

PMID: 32686665

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Proteome activity landscapes of tumor cell lines determine drug responses.

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Proteome activity landscapes of tumor cell lines determine drug responses.

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