A Landscape of Pharmacogenomic Interactions in Cancer.

Systematic studies of cancer genomes have provided unprecedented insights into the molecular nature of cancer. Using this information to guide the development and application of therapies in the clinic is challenging. Here, we report how cancer-driven alterations identified in 11,289 tumors from 29 tissues (integrating somatic mutations, copy number alterations, DNA methylation, and gene expression) can be mapped onto 1,001 molecularly annotated human cancer cell lines and correlated with sensitivity to 265 drugs. We find that cell lines faithfully recapitulate oncogenic alterations identified in tumors, find that many of these associate with drug sensitivity/resistance, and highlight the importance of tissue lineage in mediating drug response. Logic-based modeling uncovers combinations of alterations that sensitize to drugs, while machine learning demonstrates the relative importance of different data types in predicting drug response. Our analysis and datasets are rich resources to link genotypes with cellular phenotypes and to identify therapeutic options for selected cancer sub-populations.

Effective drug combinations in breast, colon and pancreatic cancer cells.

Combinations of anti-cancer drugs can overcome resistance and provide new treatments1,2. The number of possible drug combinations vastly exceeds what could be tested clinically. Efforts to systematically identify active combinations and the tissues and molecular contexts in which they are most effective could accelerate the development of combination treatments. Here we evaluate the potency and efficacy of 2,025 clinically relevant two-drug combinations, generating a dataset encompassing 125 molecularly characterized breast, colorectal and pancreatic cancer cell lines. We show that synergy between drugs is rare and highly context-dependent, and that combinations of targeted agents are most likely to be synergistic. We incorporate multi-omic molecular features to identify combination biomarkers and specify synergistic drug combinations and their active contexts, including in basal-like breast cancer, and microsatellite-stable or KRAS-mutant colon cancer. Our results show that irinotecan and CHEK1 inhibition have synergistic effects in microsatellite-stable or KRAS-TP53 double-mutant colon cancer cells, leading to apoptosis and suppression of tumour xenograft growth. This study identifies clinically relevant effective drug combinations in distinct molecular subpopulations and is a resource to guide rational efforts to develop combinatorial drug treatments.

Principal component analysis of binary genomics data.

Motivation: Genome-wide measurements of genetic and epigenetic alterations are generating more and more high-dimensional binary data. The special mathematical characteristics of binary data make the direct use of the classical principal component analysis (PCA) model to explore low-dimensional structures less obvious. Although there are several PCA alternatives for binary data in the psychometric, data analysis and machine learning literature, they are not well known to the bioinformatics community. Results: In this article, we introduce the motivation and rationale of some parametric and nonparametric versions of PCA specifically geared for binary data. Using both realistic simulations of binary data as well as mutation, CNA and methylation data of the Genomic Determinants of Sensitivity in Cancer 1000 (GDSC1000), the methods were explored for their performance with respect to finding the correct number of components, overfit, finding back the correct low-dimensional structure, variable importance, etc. The results show that if a low-dimensional structure exists in the data, that most of the methods can find it. When assuming a probabilistic generating process is underlying the data, we recommend to use the parametric logistic PCA model, while when such an assumption is not valid and the data are considered as given, the nonparametric Gifi model is recommended. Availability: The codes to reproduce the results in this article are available at the homepage of the Biosystems Data Analysis group (www.bdagroup.nl).

iTOP: inferring the topology of omics data.

Motivation: In biology, we are often faced with multiple datasets recorded on the same set of objects, such as multi-omics and phenotypic data of the same tumors. These datasets are typically not independent from each other. For example, methylation may influence gene expression, which may, in turn, influence drug response. Such relationships can strongly affect analyses performed on the data, as we have previously shown for the identification of biomarkers of drug response. Therefore, it is important to be able to chart the relationships between datasets. Results: We present iTOP, a methodology to infer a topology of relationships between datasets. We base this methodology on the RV coefficient, a measure of matrix correlation, which can be used to determine how much information is shared between two datasets. We extended the RV coefficient for partial matrix correlations, which allows the use of graph reconstruction algorithms, such as the PC algorithm, to infer the topologies. In addition, since multi-omics data often contain binary data (e.g. mutations), we also extended the RV coefficient for binary data. Applying iTOP to pharmacogenomics data, we found that gene expression acts as a mediator between most other datasets and drug response: only proteomics clearly shares information with drug response that is not present in gene expression. Based on this result, we used TANDEM, a method for drug response prediction, to identify which variables predictive of drug response were distinct to either gene expression or proteomics. Availability and implementation: An implementation of our methodology is available in the R package iTOP on CRAN. Additionally, an R Markdown document with code to reproduce all figures is provided as Supplementary Material. Supplementary information: Supplementary data are available at Bioinformatics online.

Mortality in Severe Human Immunodeficiency Virus-Tuberculosis Associates With Innate Immune Activation and Dysfunction of Monocytes.

Background: Case fatality rates among hospitalized patients diagnosed with human immunodeficiency virus (HIV)-associated tuberculosis remain high, and tuberculosis mycobacteremia is common. Our aim was to define the nature of innate immune responses associated with 12-week mortality in this population. Methods: This prospective cohort study was conducted at Khayelitsha Hospital, Cape Town, South Africa. Hospitalized HIV-infected tuberculosis patients with CD4 counts <350 cells/µL were included; tuberculosis blood cultures were performed in all. Ambulatory HIV-infected patients without active tuberculosis were recruited as controls. Whole blood was stimulated with Escherichia coli derived lipopolysaccharide, heat-killed Streptococcus pneumoniae, and Mycobacterium tuberculosis. Biomarkers of inflammation and sepsis, intracellular (flow cytometry) and secreted cytokines (Luminex), were assessed for associations with 12-week mortality using Cox proportional hazard models. Second, we investigated associations of these immune markers with tuberculosis mycobacteremia. Results: Sixty patients were included (median CD4 count 53 cells/µL (interquartile range [IQR], 22-132); 16 (27%) died after a median of 12 (IQR, 0-24) days. Thirty-one (52%) grew M. tuberculosis on blood culture. Mortality was associated with higher concentrations of procalcitonin, activation of the innate immune system (% CD16+CD14+ monocytes, interleukin-6, tumour necrosis factor-ɑ and colony-stimulating factor 3), and antiinflammatory markers (increased interleukin-1 receptor antagonist and lower monocyte and neutrophil responses to bacterial stimuli). Tuberculosis mycobacteremia was not associated with mortality, nor with biomarkers of sepsis. Conclusions: Twelve-week mortality was associated with greater pro- and antiinflammatory alterations of the innate immune system, similar to those reported in severe bacterial sepsis.

TANDEM: a two-stage approach to maximize interpretability of drug response models based on multiple molecular data types.

MOTIVATION: Clinical response to anti-cancer drugs varies between patients. A large portion of this variation can be explained by differences in molecular features, such as mutation status, copy number alterations, methylation and gene expression profiles. We show that the classic approach for combining these molecular features (Elastic Net regression on all molecular features simultaneously) results in models that are almost exclusively based on gene expression. The gene expression features selected by the classic approach are difficult to interpret as they often represent poorly studied combinations of genes, activated by aberrations in upstream signaling pathways. RESULTS: To utilize all data types in a more balanced way, we developed TANDEM, a two-stage approach in which the first stage explains response using upstream features (mutations, copy number, methylation and cancer type) and the second stage explains the remainder using downstream features (gene expression). Applying TANDEM to 934 cell lines profiled across 265 drugs (GDSC1000), we show that the resulting models are more interpretable, while retaining the same predictive performance as the classic approach. Using the more balanced contributions per data type as determined with TANDEM, we find that response to MAPK pathway inhibitors is largely predicted by mutation data, while predicting response to DNA damaging agents requires gene expression data, in particular SLFN11 expression. AVAILABILITY AND IMPLEMENTATION: TANDEM is available as an R package on CRAN (for more information, see http://ccb.nki.nl/software/tandem). CONTACT: m.michaut@nki.nl or l.wessels@nki.nl SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

A pan-cancer screen identifies drug combination benefit in cancer cell lines at the individual and population level.

Combining drugs can enhance their clinical efficacy, but the number of possible combinations and inter-tumor heterogeneity make identifying effective combinations challenging, while existing approaches often overlook clinically relevant activity. We screen one of the largest cell line panels (N = 757) with 51 clinically relevant combinations and identify responses at the level of individual cell lines and tissue populations. We establish three response classes to model cellular effects beyond monotherapy: synergy, Bliss additivity, and independent drug action (IDA). Synergy is rare (11% of responses) and frequently efficacious (>50% viability reduction), whereas Bliss and IDA are more frequent but less frequently efficacious. We introduce "efficacious combination benefit" (ECB) to describe high-efficacy responses classified as either synergy, Bliss, or IDA. We identify ECB biomarkers in vitro and show that ECB predicts response in patient-derived xenografts better than synergy alone. Our work here provides a valuable resource and framework for preclinical evaluation and the development of combination treatments.

Inhibition of the Replication Stress Response Is a Synthetic Vulnerability in SCLC That Acts Synergistically in Combination with Cisplatin.

Small cell lung cancer (SCLC) is generally regarded as very difficult to treat, mostly due to the development of metastases early in the disease and a quick relapse with resistant disease. SCLC patients initially show a good response to treatment with the DNA damaging agents cisplatin and etoposide. This is, however, quickly followed by the development of resistant disease, which urges the development of novel therapies for this type of cancer. In this study, we set out to compile a comprehensive overview of the vulnerabilities of SCLC. A functional genome-wide screen where all individual genes were knocked out was performed to identify novel vulnerabilities of SCLC. By analysis of the knockouts that were lethal to these cancer cells, we identified several processes to be synthetic vulnerabilities in SCLC. We were able to validate the vulnerability to inhibition of the replication stress response machinery by use of Chk1 and ATR inhibitors. Strikingly, SCLC cells were more sensitive to these inhibitors than nontransformed cells. In addition, these inhibitors work synergistically with either etoposide and cisplatin, where the interaction is largest with the latter. ATR inhibition by VE-822 treatment in combination with cisplatin also outperforms the combination of cisplatin with etoposide in vivo Altogether, our study uncovered a critical dependence of SCLC on the replication stress response and urges the validation of ATR inhibitors in combination with cisplatin in a clinical setting.

Genomic Determinants of Protein Abundance Variation in Colorectal Cancer Cells.

Assessing the impact of genomic alterations on protein networks is fundamental in identifying the mechanisms that shape cancer heterogeneity. We have used isobaric labeling to characterize the proteomic landscapes of 50 colorectal cancer cell lines and to decipher the functional consequences of somatic genomic variants. The robust quantification of over 9,000 proteins and 11,000 phosphopeptides on average enabled the de novo construction of a functional protein correlation network, which ultimately exposed the collateral effects of mutations on protein complexes. CRISPR-cas9 deletion of key chromatin modifiers confirmed that the consequences of genomic alterations can propagate through protein interactions in a transcript-independent manner. Lastly, we leveraged the quantified proteome to perform unsupervised classification of the cell lines and to build predictive models of drug response in colorectal cancer. Overall, we provide a deep integrative view of the functional network and the molecular structure underlying the heterogeneity of colorectal cancer cells.

Highlights from the ISCB Student Council Symposia in 2016.

This editorial provides a brief overview of the 12th International Society for Computational Biology (ISCB) Student Council Symposium and the 4th European Student Council Symposium held in Florida, USA and The Hague, Netherlands, respectively. Further, the role of the ISCB Student Council in promoting education and networking in the field of computational biology is also highlighted.