In the first systematic, largescale study to combine molecular data from patients, laboratory cancer cell lines and drug sensitivity, the researchers looked at genetic mutations known to cause cancer in more than 11,000 patient samples of 29 different tumour types. Hcc827 is an egfr exon19del mutant lung cancer cell line sensitive to. The cancer cell proteome and transcriptome predicts. The genomics of drug sensitivity of cancer gdsc database now contains data for an extra 187 drugs and more than 160,000 new unique compound cell line pairs.
A biomarker harvest from one thousand cancer cell lines. Quantification of sensitivity and resistance of breast. With many recent advances, cancer cell culture research is more important than ever before. Comparison of dna copynumber profiles gistic gscores between cell lines and primary tumors. On this website, you will find drug response data and genomic markers of sensitivity. First, the researchers engineered a mouse cell line to be sensitive or resistant to the targeted drug imatinib gleevec. The cancer types are those described by the cancer genome atlas tcga. The genomics of drug sensitivity in cancer project is a collaboration between the cancer genome project at the wellcome sanger institute uk and the center for molecular therapeutics, massachusetts general hospital cancer center usa. Assays in which immortalized cell lines are exposed to. Distribution of cancer types in the ccle by lineage. Robustness of our model was validated by crossvalidation and an independent dataset, the cancer genome project cgp. Colorectal cancer cell line proteomes are representative. Pharmacogenomic agreement between two cancer cell line data sets. In order to determine the cell death caused by these mechanisms, there is a need for cheap, reliable and reproducible shortterm cytotoxicity and cell viability assays.
Predictive modeling of drug sensitivity gives an overview of drug sensitivity modeling for personalized medicine that includes data characterizations, modeling techniques, applications, and research challenges. The resulting collection, which we termed the cancer cell line encyclopedia ccle, encompasses 36 tumour types fig. Overcoming cancer evolution with collateral sensitivity and. The increasing availability of in vitro sensitivity and cell line profiling data sets raises the question of whether this information could be used, and to which extent, to.
The models were then tested in the excluded cell lines. As the nci60 only involves five breast cancer cell lines, which only partially reflect the distinct subtypes, we performed the same analysis on the more comprehensive cancer cell line encyclopedia ccle. Measuring cancer drug sensitivity and resistance in cultured cells. Methods and protocols, expert researchers describe in detail their most productive and uptodate methods for growing cancer cells in the laboratory. Established cell lines were from the atcc and cultured using published methodology. C pan cancer drug sensitivity predictions using either genomictranscriptomicproteomic data or tumor type. A pancancer analysis of progression mechanisms and drug. Drug sensitivity in cancer cell lines is not tissue. Drug sensitivity in cancer cell lines is not tissuespecific. These proteins can recapitulate mutational patterns seen in patients and show ability to predict drug sensitivity. We assess whether drug sensitivity in cancer cell lines is able to discriminate tissue specificity. Ccle cancer cell line encyclopedia provides a compilation of gene expression, chromosomal copy number, and massively parallel sequencing data from human cancer cell lines.
Mar 29, 2012 the cancer cell line encyclopedia ccle a. Barretina j, caponigro g, stransky n et al 2012 the cancer cell line encyclopedia enables predictive modelling of anticancer drug sensitivity. What is the name of an article which is against the the. Sep 15, 2016 for example, cell lines were used for the preclinical development of the smallmolecule egfr inhibitor gefitinib, which is approved for the treatment of egfrmutated nonsmall cell lung cancer 1, 2. The cancer cell line encyclopedia enables predictive. Cancer cell lines predict drug response wellcome sanger. From the available 19,000 gene expressions we use relieff to screen top 250 features.
These large cell line datasets provide a more comprehensive representation of the genomics variability observed in tumors. Drug combinations to overcome treatment resistance national. In each study, aucs are provided, measuring the relationship between drug concentration and cell viability. Conversely, midostaurin, a targeted drug against hrpositive tumors, only shows activity in triplenegative cell lines. T wo things are required for the generation of reproducible and useful drug. Sokilde r, kaczkowski b, podolska a, cirera s, gorodkin j, moller s, and litman t. Current trends in drug sensitivity prediction bentham science. The team created a microfluidic cell culture device that allows the direct, realtime observation of the development of drug resistance in cancer cells. This large collection of cell lines enabled us to capture much of the genomic heterogeneity that underlies human cancer, and which appears to play a critical role in determining the variable response of patients to treatment with specific agents. How to determine the cancer cells sensitivity to certain drugs. Genomics of drug sensitivity in cancer cancerrxgene. These large cell line datasets provide a more comprehensive representation of the genomics variability observed in tumors providing new means to identify novel drug targets or drug response.
The analysis of anticancer drug sensitivity of lung cancer. To study the relationship between biomarkers such as braf mutation status and drug sensitivity, the cell line panel was subjected to 109 different drugs, representing a wide range of substances targeting, among others, the mapk pathway, the pi3kakt pathway, as well as mitotic and metabolic processes. Expression levels of therapeutic targets as indicators of. Anticancer drug sensitivity prediction in cell lines from.
Clustering facility also allow users to identify promiscous drugs effectice against wide range of cell lines or cancer types. We have characterised human cancer cell lines and screened them with 100s of compounds. Aug 31, 2017 a new cell culture system that provides a tool for preclinical cancer drug development and screening has been developed by american researchers. To this aim, we here used gene expression features and drug sensitivity data in cancer cell line encyclopedia ccle to build a predictor based on support vector machine svm and a recursive feature selection tool. Cancer cell line drug sensitivity data are generated from ongoing highthroughput screening performed by the cancer genome project at the wellcome trust sanger institute wtsi and the center for molecular therapeutics at massachusetts general hospital using a collection of cell lines. Predictive modeling of drug sensitivity sciencedirect.
Here we show substantial agreement and biological consilience between drug sensitivity measurements and their associated genomic predictors from two publicly available largescale pharmacogenomics. It covers the major mathematical techniques used for modeling drug sensitivity, and includes the requisite biological knowledge to. B comparison of crossvalidation model r 2 values cell line based with t test signed log p values of cell line sclc versus luad true drug sensitivities ic 50. Writing the book of cancer knowledge here there be dependencies.
We find that cancer specific drugs do not show higher efficacies in cell lines representing the. For this study, the research team wanted to determine if measuring mar following cancer treatment could rapidly and accurately predict cancer cell death or growth. A sensitivity of cancer specific drugs intended for breast cancer 41, colorectal cancer 24 and prostate cancer 38 across the nci60 panel covering 59 cancer cell lines derived from nine cancer tissues. They also demonstrated that treatment with only one drug of. In the first systematic, largescale study to combine molecular data from patients, laboratory cancer cell lines and drug sensitivity, the researchers looked at genetic mutations known to cause. For each cell line, the researchers identified an average of 3. Here we show substantial agreement and biological consilience between drug sensitivity measurements and their associated genomic predictors from two publicly available largescale pharmacogenomics resources. When coupled with pharmacological profiles for 24 anticancer drugs across 479 of the cell lines, this collection allowed identification of genetic, lineage. The cancer cell line encyclopedia enables predictive modelling of anticancer drug sensitivity. Large cancer cell line based projects, such as nci60,7 cancer cell line encyclopedia ccle,2 and genomics of drug sensitivity in cancer gdsc,3 have used molecularly heterogeneous authors share co. Cancer cell lines are the most commonly utilized model systems in tumor biology and therapy development. Machine learning prediction of cancer cell sensitivity to. What are the model cell lines for studying an anticancer. Red cells indicate high activity while green cells indicate inactivity.
The importance of cancer cell lines as in vitro models in cancer methylome analysis and anticancer drugs testing 143 tumour. The genomics of drug sensitivity in cancer provides public access to data on the sensitivity of genomically characterized cancer cell lines to. Halgamuge, azeem mohammad school of computing and mathematics charles sturt university melbourne, victoria 3000, australia abstractlung cancer is the commonest type of cancer with. The gi50 represents the negative log of the concentration that is required to inhibit the growth of a cell line. This is an increase of 70% compared to previous releases. Measuring cancer drug sensitivity and resistance in. The xenografts models nude mice are used for testing the tumorigenicity and metastatic ability of cancer cell lines. The gi50 represents the negative log of the concentration that is required to inhibit the growth of a cell line by 50%. Datasets cell line numbers i the genomics of drug sensitivity in cancer project is a collaboration between the cancer genome project at the wellcome sanger institute uk and the center for molecular therapeutics, massachusetts general hospital cancer center usa. Pharmacogenomic agreement between two cancer cell line.
Predict drug sensitivity of cancer cells with pathway. In vitro cell viability and cytotoxicity assays with cultured cells are widely used for cytotoxicity tests of chemicals and for drug screening. When coupled with pharmacologic profiles for 24 anticancer drugs across 479 of the lines, this collection allowed identification of genetic, lineage, and. Studies expand and update an encyclopedia of cancer cell. The first volume of a book of cancer knowledge has been published, which scientists say will speed up the search for new cancer drugs. Here we describe the cancer cell line encyclopedia ccle. Large cancer cell line based projects, such as nci60, 7 cancer cell line encyclopedia ccle, 2 and genomics of drug sensitivity in cancer gdsc, 3 have used molecularly heterogeneous cancer cell lines to identify stratification biomarkers and signatures for precision medicine. The ccle provides public access analysis and visualization of dna copy number, mrna expression, mutation data and more, for cancer cell lines. Characterization of human cancer cell lines by reverse. For each cancer cell line, the expression of the drug target in the untreated cells and the corresponding sensitivity value of that cell line to that drug were extracted.
Writing the book of cancer knowledge harvard gazette. A cancer specific analysis correlates drug sensitivity for cancer cell lines of the specified cancer type with genomic features identified in patients from the designated cancer type. Mar 28, 2012 the cancer cell line encyclopedia presents the first results from a largescale screen of some 947 cancer cell lines with 24 anticancer drugs, with the aim of identifying specific genomic. In order to test our theory on real dataset, we obtain gene expression and normalized area under the curve auc values for the cell lines tested on the drug 17aag from the cancer cell line encyclopedia ccle. Quantification of sensitivity and resistance of breast cancer cell lines to anti cancer drugs using gr metrics skip to main content thank you for visiting. Graphic concept by francesco iorio, illustration by spencer phillips, emblebi cancer cell lines predict drug response 5 jul 2016 15. The cancer cell line encyclopedia enables predictive modelling of anticancer drug sensitivity article pdf available in nature 4837391. Resistant populations were obtained for the four cell lines through lifetime exposure to the drug for a minimum of 3 months in the case of the line skbr3, 7 months in the case of the au565 and efm192a lines, and 8 months in the case of the bt474 line. Proteomic data tend to exhibit improved prediction of drug sensitivity as compared with genomic and transcriptomic profiles. Cancer cell lines predict drug response and accelerate.
The cancer cell line encyclopedia ccle project is an effort to conduct a detailed genetic characterization of a large panel of human cancer cell lines. Combining molecular data from patients, laboratory cancer cell lines and drug sensitivity to improve precision medicine. Drug sensitivity in cancer cell lines is not tissuespecific samira jaeger1, miquel duranfrigola1 and patrick aloy1,2 abstract background. Exploiting evolutionary steering to induce collateral drug sensitivity in cancer. As an example, tomlinson and colleagues 1998 compared a breast primary tumour and a cell line originated from that tumour. The growing of cancer cells in the laboratory has been a powerful tool for studying and understanding the biology of cancer and the effects of drugs on cancer cells. Putting cancers vulnerabilities on the map cancer cell lines evolve in ways that affect how they respond to drugs loss of a dna repair system creates a unique vulnerability in many cancer types.
The us national cancer institute nci 60 human tumour cell line anticancer drug screen nci60 was developed in the late 1980s as an in vitro drug discovery tool intended to supplant the use of. The cancer cell line encyclopedia provides public access to genomic data, analysis and visualization for about cell lines. Drug sensitivity assays of human cancer organoid cultures. This is why old cell growthbased assays didnt work and why cell deathbased assays do. Pancancer convergence to a smallcell neuroendocrine. R 2 values are from true cell line drug sensitivities versus crossvalidationbased predicted cell line sensitivities.
The sensitivity patterns of the cell lines were correlated with extensive genomic and expression data to identify genetic features that are predictive of sensitivity. Cancer cell line panels have proved useful disease models to, among others, identify genomic markers of drug sensitivity and to develop new anticancer drugs. Tissue specificity displayed by canerspecific drugs. Proteomes of established crc cell line are representative of primary tumors. The analysis of anticancer drug sensitivity of lung cancer cell lines by using machine learning clustering techniques chandi s.
The ubc40 urothelial bladder cancer cell line index. D all cell lines belonging to the tumor type specified by the xaxis were excluded and the remaining cell lines used for building drug sensitivity models cross. More recently, the scale of cancer cell line drug screens has expanded dramatically e. Later, studies like cancer cell line encyclopedia ccle, genomic drug sensitivity of cancer gdsc and gsk panel have extended to largescale collection of cell lines with drug responses and more molecular data types. Primary cell models were established and cultured on collagencoated tissue culture plates in supplemented ksf media. Cancer cell lines have a prominent role in the initial stages of drug discovery, facilitating highthroughput screening of potential drugs. Cells were passaged by trypsinization and used at early passage p 20 for the analysis of drug sensitivity. Patientspecific cancer cell lines designed to predict.
Garraway, a senior associate member of the broad institute, an associate professor at harvard medical school and danafarber cancer institute, and a co. Thus, it is difficult to predict clinical anti cancer efficacy only by relying on the genomic information of cell lines i. Sensitivity of drugs indicated for hormone receptor positive, triple negative and her2overexpressing breast cancer within 30 breast cancer cell lines representing the different subtypes. Exploiting evolutionary steering to induce collateral drug. Nonetheless, controversy remains whether cell lines provide an. Clustering of cell lines based on their drug sensitivity allow users to identify group of cell lines, which are resistance for a particular anticancer drug. Trastuzumab was dissolved in sterile water at a stock concentration of 20 mgml.
Our integrative proteogenomic analysis highlights the potential of proteome profiling to inform personalized cancer medicine. This sample is limited in amount and the genetic manipulation is almost impossible 3. The cancer cell line encyclopedia and the genomics of drug sensitivity in cancer databases. I am find an article where its opinion is against the cancer cell line encyclopedia enables predictive modelling of anticancer drug sensitivity.
Furthermore, analysis of molecular correlates of drug sensitivity in the cell lines identified multiple known features, including tissue type lineage, as top predictors of sensitivity to several agents. This large collection of cell lines enabled us to capture much of the genomic heterogeneity that underlies human cancer, and which appears to play a critical role in determining. The study concluded that the cell lines may provide representative genetic proxies for primary tumors in many cancer types. Faq cancerrxgene genomics of drug sensitivity in cancer. The importance of cancer cell lines as in vitro models in cancer methylome analysis and anticancer drugs testing 141 tissues 8. Cell line drug sensitivity was measured as the concentration at which the drug inhibited 50 % of the cellular growth ic 50. May 01, 2017 this detailed growing understanding of the dynamics of cancer cell reaction to drug treatment regimes joins a growing school of potential cancer therapies guided by an understanding of cancer evolution, such as the approach by bob gatenby and colleagues at the moffitt, which suggests that the careful titration of low dose cancer therapy so.
For this analysis, we have determined the relative sensitivity z score of a cell line to a given drug compared to all other cell lines. The resulting collection encompasses 36 tumor types. We integrated both genomic features of cell lines and chemical information of compounds to predict the half maximal inhibitory concentrations ic50 on the cancer cell line encyclopedia ccle and the genomics of drug sensitivity in cancer gdsc datasets using a deep neural network, which we called deepdsc. Methods and protocols covers the basic concepts of cancer cell biology and culture while expanding upon the recent shift in cell culture methods from the generation of new cell lines to the use of primary cells. The diagonal of the heatmap shows the pearson correlation between corresponding sample types. Cancerrxgene genomics of drug sensitivity in cancer. Cancer cell lines predict drug response 5 jul 2016 15. However, their clinical relevance remains controversial.