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A meta-analysis approach for characterizing pan-cancer mechanisms of drug sensitivity in cell lines.

ABSTRACT: Understanding the heterogeneous drug response of cancer patients is essential to precision oncology. Pioneering genomic analyses of individual cancer subtypes have begun to identify key determinants of resistance, including up-regulation of multi-drug resistance (MDR) genes and mutational alterations of drug targets. However, these alterations are sufficient to explain only a minority of the population, and additional mechanisms of drug resistance or sensitivity are required to explain the remaining spectrum of patient responses to ultimately achieve the goal of precision oncology. We hypothesized that a pan-cancer analysis of in vitro drug sensitivities across numerous cancer lineages will improve the detection of statistical associations and yield more robust and, importantly, recurrent determinants of response. In this study, we developed a statistical framework based on the meta-analysis of expression profiles to identify pan-cancer markers and mechanisms of drug response. Using the Cancer Cell Line Encyclopaedia (CCLE), a large panel of several hundred cancer cell lines from numerous distinct lineages, we characterized both known and novel mechanisms of response to cytotoxic drugs including inhibitors of Topoisomerase 1 (TOP1; Topotecan, Irinotecan) and targeted therapies including inhibitors of histone deacetylases (HDAC; Panobinostat) and MAP/ERK kinases (MEK; PD-0325901, AZD6244). Notably, our analysis implicated reduced replication and transcriptional rates, as well as deficiency in DNA damage repair genes in resistance to TOP1 inhibitors. The constitutive activation of several signaling pathways including the interferon/STAT-1 pathway was implicated in resistance to the pan-HDAC inhibitor. Finally, a number of dysregulations upstream of MEK were identified as compensatory mechanisms of resistance to the MEK inhibitors. In comparison to alternative pan-cancer analysis strategies, our approach can better elucidate relevant drug response mechanisms. Moreover, the compendium of putative markers and mechanisms identified through our analysis can serve as a foundation for future studies into these drugs.

SUBMITTER: Wang K

PROVIDER: S-EPMC4103868 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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A meta-analysis approach for characterizing pan-cancer mechanisms of drug sensitivity in cell lines.

Wang Kendric K Shrestha Raunak R Wyatt Alexander W AW Reddy Anupama A Lehár Joseph J Wang Yuzhou Y Lapuk Anna A Collins Colin C CC

PloS one 20140718 7

Understanding the heterogeneous drug response of cancer patients is essential to precision oncology. Pioneering genomic analyses of individual cancer subtypes have begun to identify key determinants of resistance, including up-regulation of multi-drug resistance (MDR) genes and mutational alterations of drug targets. However, these alterations are sufficient to explain only a minority of the population, and additional mechanisms of drug resistance or sensitivity are required to explain the remai ...[more]

PMID: 25036042

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Project description:Drug sensitivity prediction models for human cancer cell lines constitute important tools in identifying potential computational biomarkers for responsiveness in a pre-clinical setting. Integrating information derived from a range of heterogeneous data is crucial, but remains non-trivial, as differences in data structures may hinder fitting algorithms from assigning adequate weights to complementary information that is contained in distinct omics data. In order to counteract this effect that tends to lead to just one data type dominating supposedly multi-omics models, we developed a novel tool that enables users to train single-omics models separately in a first step and to integrate them into a multi-omics model in a second step. Extensive ablation studies are performed in order to facilitate an in-depth evaluation of the respective contributions of singular data types and of combinations thereof, effectively identifying redundancies and interdependencies between them. Moreover, the integration of the single-omics models is realized by a range of distinct classification algorithms, thus allowing for a performance comparison. Sets of molecular events and tissue types found to be related to significant shifts in drug sensitivity are returned to facilitate a comprehensive and straightforward analysis of potential computational biomarkers for drug responsiveness. Our two-step approach yields sets of actual multi-omics pan-cancer classification models that are highly predictive for a majority of drugs in the GDSC data base. In the context of targeted drugs with particular modes of action, its predictive performances compare favourably to those of classification models that incorporate multi-omics data in a simple one-step approach. Additionally, case studies demonstrate that it succeeds both in correctly identifying known key biomarkers for sensitivity towards specific drug compounds as well as in providing sets of potential candidates for additional computational biomarkers.

Project description:Motivation:Proteomics profiling is increasingly being used for molecular stratification of cancer patients and cell-line panels. However, systematic assessment of the predictive power of large-scale proteomic technologies across various drug classes and cancer types is currently lacking. To that end, we carried out the first pan-cancer, multi-omics comparative analysis of the relative performance of two proteomic technologies, targeted reverse phase protein array (RPPA) and global mass spectrometry (MS), in terms of their accuracy for predicting the sensitivity of cancer cells to both cytotoxic chemotherapeutics and molecularly targeted anticancer compounds. Results:Our results in two cell-line panels demonstrate how MS profiling improves drug response predictions beyond that of the RPPA or the other omics profiles when used alone. However, frequent missing MS data values complicate its use in predictive modeling and required additional filtering, such as focusing on completely measured or known oncoproteins, to obtain maximal predictive performance. Rather strikingly, the two proteomics profiles provided complementary predictive signal both for the cytotoxic and targeted compounds. Further, information about the cellular-abundance of primary target proteins was found critical for predicting the response of targeted compounds, although the non-target features also contributed significantly to the predictive power. The clinical relevance of the selected protein markers was confirmed in cancer patient data. These results provide novel insights into the relative performance and optimal use of the widely applied proteomic technologies, MS and RPPA, which should prove useful in translational applications, such as defining the best combination of omics technologies and marker panels for understanding and predicting drug sensitivities in cancer patients. Availability and implementation:Processed datasets, R as well as Matlab implementations of the methods are available at https://github.com/mehr-een/bemkl-rbps. Contact:mehreen.ali@helsinki.fi or tero.aittokallio@fimm.fi. Supplementary information:Supplementary data are available at Bioinformatics online.

Project description:MicroRNAs (miRNAs) regulate gene expression post-transcriptionally. In this way they might influence whether a cell is sensitive or resistant to a certain drug. So far, only a limited number of relatively small scale studies comprising few cell lines and/or drugs have been performed. To obtain a broader view on miRNAs and their association with drug response, we investigated the expression levels of 411 miRNAs in relation to drug sensitivity in 36 breast cancer cell lines. For this purpose IC50 values of a drug screen involving 34 drugs were associated with miRNA expression data of the same breast cancer cell lines. Since molecular subtype of the breast cancer cell lines is considered a confounding factor in drug association studies, multivariate analysis taking subtype into account was performed on significant miRNA-drug associations which retained 13 associations. These associations consisted of 11 different miRNAs and eight different drugs (among which Paclitaxel, Docetaxel and Veliparib). The taxanes, Paclitaxel and Docetaxel, were the only drugs having miRNAs in common: hsa-miR-187-5p and hsa-miR-106a-3p indicative of drug resistance while Paclitaxel sensitivity alone associated with hsa-miR-556-5p. Tivantinib was associated with hsa-let-7d-5p and hsa-miR-18a-5p for sensitivity and hsa-miR-637 for resistance. Drug sensitivity was associated with hsa-let-7a-5p for Bortezomib, hsa-miR-135a-3p for JNJ-707 and hsa-miR-185-3p for Panobinostat. Drug resistance was associated with hsa-miR-182-5p for Veliparib and hsa-miR-629-5p for Tipifarnib. Pathway analysis for significant miRNAs was performed to reveal biological roles, aiding to find a potential mechanistic link for the observed associations with drug response. By doing so hsa-miR-187-5p was linked to the cell cycle G2-M checkpoint in line with this checkpoint being the target of taxanes. In conclusion, our study shows that miRNAs could potentially serve as biomarkers for intrinsic drug resistance and that pathway analyses can provide additional information in this context.

Dataset Information

A meta-analysis approach for characterizing pan-cancer mechanisms of drug sensitivity in cell lines.

Publications

A meta-analysis approach for characterizing pan-cancer mechanisms of drug sensitivity in cell lines.

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