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.

Data-independent acquisition-based proteome and phosphoproteome profiling across six melanoma cell lines reveals determinants of proteotypes

“…This study leveraged a systematic view of proteotype co-variation networks determined by genomic factors in colorectal cancer 5 . Also, the proteome maps of NCI-60 cell lines were analyzed by different MS techniques [6][7][8] . On the other hand, others and we have reported the instability of cell lines, both genetic and phenotypic, even for the cells of the same name between different laboratories 9,10 .…”

“…As above, there are pressing needs for both high-throughput characterization of multiple cells and proteomic documentation of individual cells. Furthermore, because dynamic phosphorylation plays a major role in regulating many cellular processes, phosphoproteomic profiling was recently used in defining the proteome "activity" in cancer cell line panels 8 . Together, it is imperative to establish a fast, cost-effective, reproducible method for profiling the cell "proteotype" 12 , ideally through both proteome and phosphoproteome profiling.…”

Data-independent Acquisition-based Proteome and Phosphoproteome Profiling across Six Melanoma Cell Lines Reveals Determinants of Proteotypes

“…This study leveraged a systematic view of proteotype co-variation networks determined by genomic factors in colorectal cancer 5 . Also, the proteome maps of NCI-60 cell lines were analyzed by different MS techniques [6][7][8] . On the other hand, others and we have reported the instability of cell lines, both genetic and phenotypic, even for the cells of the same name between different laboratories 9,10 .…”

“…Together, it is imperative to establish a fast, cost-effective, reproducible method for profiling the cell "proteotype" 12 , ideally through both proteome and phosphoproteome profiling. Previously, the integrative proteomic and phosphoproteomic measurements have been successfully performed by coupling peptide-fractionation to either shotgun-or TMT-MS workflows in cancer cell lines and clinical tissues 5,8,[13][14][15][16] . The dataindependent acquisition mass spectrometry (DIA-MS) [17][18][19] provides an alternative, simple, and robust MS workflow for profiling proteotype through the concurrent proteomic and phosphoproteomic analysis 20 , without the need of extensive peptide-level fractionation and the costly tagging reagents.…”

Quantitative proteomics characterization of cancer biomarkers and treatment

“…Adenylate kinase isoenzyme 1 (AK1) was discovered as a promising drug target for acute myeloid leukemia patients. 76 The anaplastic lymphoma kinase (ALK) inhibitor ceritinib was found to be capable of modulating the protein-trafficking and degradation-related process of autophagy after the quantitative analysis of five lung cancer cell lines in response to more than 50 drugs. 77 The proto-oncogene serine/threonine-protein kinase PIM3 has been widely used as a drug target.…”