As precision medicine demands molecular determinants of drug response, CellMinerCDB provides (https://discover.nci.nih.gov/cellminercdb/) a web-based portal for multiple forms of pharmacological, molecular, and genomic analyses, unifying the richest cancer cell line datasets (NCI-60, NCI-SCLC, Sanger/MGH GDSC, and Broad CCLE/CTRP). CellMinerCDB enables genomic and pharmacological data queries for identifying pharmacogenomic determinants, drug signatures, and gene regulatory networks for researchers without requiring specialized bioinformatics support. It leverages overlaps of cell lines and tested drugs to allow assessment of data reproducibility. It builds on the complementarity and strength of each dataset. A panel of 41 drugs evaluated in parallel in the NCI-60 and GDSC is reported, supporting drug reproducibility across databases, repositioning of bisacodyl and acetalax for triple negative breast cancer, and identifying novel drug response determinants and genomic signatures for topoisomerase inhibitors and schweinfurthins in development. CellMinerCDB also allowed the identification of LIX1L as a novel mesenchymal gene regulating cellular migration and invasiveness.A critical aim of precision medicine is to match drugs with genomic determinants of response.Associating tumor sample molecular features with the response to specific drug treatments is especially challenging because of the typically encountered diversity of patient experiences, partial knowledge of the multiple molecular determinants of response and resistance downstream from the primary drug targets, and tumor heterogeneity. In this setting, the relative homogeneity of cell populations in cancer cell lines is advantageous, making them a starting point for resolving and establishing cell intrinsic drug response mechanisms. These features motivate the expanded development of cancer cell line pharmacogenomic databases.Building on the paradigm introduced by the NCI-60 (1,2), pharmacogenomic data portals such the Genomics of Drug Sensitivity in Cancer (GDSC) (3,4), the Cancer Cell Line Encyclopedia (CCLE) (5), and the Cancer Therapeutics Response Portal (CTRP) (6) have expanded to span ~1000 cancer cell lines.Each database provides a readily available resource for translational research, and proposals have been advanced to further enrich them to over 10,000 cancer cell lines for better coverage of tumor type diversity (7). The CellMiner NCI-60 dataset includes drug activity data for over 21,000 compounds, together with a wide range of molecular profiling data (gene expression, mutations, copy number, methylation, and protein expression). The GDSC and CCLE collections focus on drug activity data for clinically relevant drugs over larger cell line sets, together with an array of molecular profiling data that match the NCI-60 and clinical genomic analyses. The CTRP provides independent drug activity data for nearly 500 compounds over cell lines spanning most of the CCLE and GDSC collections. The sourcespecific portals allow deep exploration of their asso...
52We describe the rapid and reproducible acquisition of quantitative proteome maps for the 53 NCI-60 cancer cell lines and their use to reveal cancer biology and drug response 54 determinants. Proteome datasets for the 60 cell lines were acquired in duplicate within 30 55 working days using pressure cycling technology and SWATH mass spectrometry. We 56 consistently quantified 3,171 SwissProt proteotypic proteins across all cell lines, generating a 57 data matrix with 0.1% missing values, allowing analyses of protein complexes and pathway 58 activities across all the cancer cells. Systematic and integrative analysis of the genetic 59 variation, mRNA expression and proteomic data of the NCI-60 cancer cell lines uncovered 60complementarity between different types of molecular data in the prediction of the response to 61 240 drugs. We additionally identified novel proteomic drug response determinants for 62 clinically relevant chemotherapeutic and targeted therapies. We anticipate that this study 63 represents a landmark effort toward the translational application of proteotypes, which reveal 64 biological insights that are easily missed in the absence of proteomic data. 65 96 consistently quantified 3,171 SwissProt proteotypic proteins across all cell lines, generating a 97 data matrix (120 proteomes vs. 3171 proteins) with 0.1% missing values. Raw signals of each 98 peptide and protein in each sample were curated with an expert system. The NCI-60 human 99 5 cancer cell line panel contains 60 lines from 9 different tissue types 12 . The NCI-60 have been 100 molecularly and pharmacologically characterized with unparalleled depth and coverage, 101 offering a prime in vitro model to further our understanding of cancer biology and cellular 102 responses to anti-cancer agents 12, 13 . Discoveries enabled by the NCI-60 in recent years 103 include the development of the FDA approved drugs oxaliplatin for the treatment of colon 104 cancers 14 , eribulin for metastatic breast cancers 12 , bortezomib for the treatment of multiple 105 myeloma 15 , and rhomidepsin for cutaneous T-cell lymphomas 16 . The sensitivity of the NCI-106 60 has been measured for over 100,000 synthetic or natural compounds derived from a wide 107 range of academic and industrial sources 12 , constructing the most comprehensive resource for 108 cancer pharmacological research. The proteomic data complement the existing NCI-60 109 molecular landscapes, allowing systematic investigation of the complementarity among 110 genomics, transcriptomics and proteomics in a number of applications. 111 112 The proteome of the NCI-60 cells has been analyzed previously by data dependent 113 analysis (DDA), a commonly used discovery mass spectrometry technique 17 . Whereas the 114 study reported the cumulative identification of 10,350 IPI proteins from about 1,000 115 fractionated and kinase-enriched sample runs, only 492 IPI proteins were quantified across the 116 NCI-60 cell lines without missing value. The present study thus extends the number of 117 consistently qua...
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