- Open Access
Context-specific functional module based drug efficacy prediction
© Hwang et al. 2016
- Published: 28 July 2016
It is necessary to evaluate the efficacy of individual drugs on patients to realize personalized medicine. Testing drugs on patients in clinical trial is the only way to evaluate the efficacy of drugs. The approach is labour intensive and requires overwhelming costs and a number of experiments. Therefore, preclinical model system has been intensively investigated for predicting the efficacy of drugs. Current computational drug sensitivity prediction approaches use general biological network modules as their prediction features. Therefore, they miss indirect effectors or the effects from tissue-specific interactions.
We developed cell line specific functional modules. Enriched scores of functional modules are utilized as cell line specific features to predict the efficacy of drugs. Cell line specific functional modules are clusters of genes, which have similar biological functions in cell line specific networks. We used linear regression for drug efficacy prediction. We assessed the prediction performance in leave-one-out cross-validation (LOOCV). Our method was compared with elastic net model, which is a popular model for drug efficacy prediction. In addition, we analysed drug sensitivity-associated functions of five drugs - lapatinib, erlotinib, raloxifene, tamoxifen and gefitinib- by our model.
Our model can provide cell line specific drug efficacy prediction and also provide functions which are associated with drug sensitivity. Therefore, we could utilize drug sensitivity associated functions for drug repositioning or for suggesting secondary drugs for overcoming drug resistance.
There are two types of methods for identifying the efficacy of a drug; clinical trials and computational methods. Although clinical trial is much accurate in assessing drug efficacy and toxicity, it requires overwhelming cost and a number of tests. Also, there is a limitation in experimental method, for it cannot predict the efficacy of a new drug. So, we need to conduct same overall process of clinical trial to identify the efficacy of a new drug.
There are, accordingly, many computational methods which predict the efficacy of a new drug using genomic data [2, 3]. With the recent advances biological experimental technologies, large collections of matched drug screens and genomics profiles of cancer cell lines have been published [4, 5]. These data have been used to build drug efficacy prediction models by associating genomic features with drug sensitivity in cancer cell lines [6–9]. These previous studies used single gene or multi genes as associated genomic features for predicting drug efficacy.
In tumorigenesis, diverse patterns of mutation, gene expression have been observed in cancer-specific, or tissue - specific manner . Diverse patterns of genomic features according to the biological contexts play an important role in clinical efficacy. Recently it has been found that biological networks can be rewired according to biological contexts, such as genotype and phenotype [11–14]. With network rewiring, drug responses in each person can be changed . For example, in Gefitinib-sensitive cancers, RAS,MEK/ERK and PI3K/AKT signaling pathways are suppressed, resulting in cell cycle arrest and apoptosis. In Gefitinib-resistant cancers with network rewiring, the secondary RTK, which is not a target of Gefitinib, reactivates RAS,MEK/ERK and PI3K/AKT signaling pathways. Sustained activations of these pathways result in cell proliferation and survival in the presence of Gefitinib.
Previous methods used known gene sets or known pathways as their features for predicting drug efficacy. Therefore, those methods cannot consider network rewiring.
By considering network rewiring and biological context, we can enhance the accuracy in predicting drug efficacy. We assume that each cell line has differently activated gene set of same biological functions, so if activated gene sets of each cell line are similar, the drug efficacy of cell lines is similar. For instance, activated gene sets of apoptosis are similar in cell line1 and cell line 2. In this case, the efficacy of Lapatinib, a drug related to apoptosis, will be similar in both cell line 1 and cell line 2. To be generalized, this method comparing the functions of a drug and the functions associated to the activated gene sets in a cell line explains the efficacy and related biological functions of a drug.
Here, we aim to develop a method considering network rewiring and biological context to predict the efficacy of drugs. This method will suggest personalized medicines based on genomic information.
We used gene expression data of NCI-60 , a panel of 60 diverse human cancer cell lines. The gene expression data of 9 different cancer types is from GSE32474 and GSE34211 in GEO database. We normalized the gene expression data of cancer samples from each cell line, which passed quality check, by GCRMA. The gene expression data of 9 normal tissues are arranged from GSE21422, GSE15824, GSE8671, GSE48060, GSE30999, GSE11842, GSE14407, GSE55945, and E-TABM-282, respectively, in GEO and arrayexpress databases. We normalized the gene expression data of normal samples which passed quality check, by GCRMA.
Biological network construction
We constructed a backbone network by integrating public databases, which are BioGrid , KEGG , and TRANFAC . The constructed backbone network includes various types of interactions such as protein-protein interactions and gene regulatory interactions. The backbone network has 12,849 nodes and 300,507 interactions.
Context-specific function module
We used MCL for clustering the backbone network. MCL is a graph clustering using flow simulation. Several researches utilized and proved that MCL generates robust cluster functional modules from given biological networks [20–23]. Through MCL, we could generate MCL functional modules of the backbone network. We assigned absolute value of PCC of the two genes connected in the network as edge weights. We used 2.5 as the inflation coefficient. For analysing the clustering result, we chose MCL modules of size greater than 8.
A function vector is a vector containing GO terms that are enriched on genes of a functional module. Each functional module has multiple enriched GO terms, which are biological functions. Therefore, it is difficult to identify the function of a functional module.
Context-specific function detection
Fifth, we added GI50, which is drug concentration required to reduce growth rates to 50 % of the maximum rate, values of drugs as drug response values.
Context-specific functional module
To make context-specific function modules, we first construct context-specific networks that mean cell line-specific networks in this work. We calculate the Pearson correlation coefficients (PCCs) for all interactions in the backbone network to construct context-specific networks. The criteria for context-specific interaction is greater than p-value 0.01 of PCCs. Then we assign values of PCCs as edge weights of context-specific network. Next, we use network clustering algorithm, MCL (Markov clustering) , to detect functional modules in the weighted context-specific network. MCL algorithm cluster weighted network by making strongly correlated edges to get stronger and making weakly correlated edges to get weaker. Thereby, only strongly correlated edges are survived.
The MCL clusters many network modules, the majority of which are very small, and contain two or three genes only. we filtered the modules by an arbitrary threshold n and selected n = 8 by reference .
Context-specific functional module has more than one enriched GO biological processes. Thereby, it is difficult to identify related function of a context-specific functional module. For example, “MCF Module 1”, which is one of context-specific functional modules, has three enriched GO biological processes, which are “GO: 1234”, “GO:156” and “GO:3249”. Enriched GO biological processes of “MCF Module 2” are “GO: 1234”, “GO: 145” and “GO: 3244”. A drug efficacy prediction model of Gefitinib suggests that “GO:1234” is associated with efficacy of Gefitinib. Then, we cannot identify whether related function of Gefitinib efficacy is “MCF Module 1” or “MCF Module 2”. To avoid this ambiguousness, we define a GO vector for mapping one context-specific function module to a function. The GO vector is called context-specific function vector in this work. In this example, the context-specific function vector of ‘MCF Module 1” is [“GO: 1234”, “GO: 156”, “GO: 3249”]. We assign context-specific function vector of context-specific functional module by module similarity method.
Context-specific function vectors
RNA splicing, via transesterification reactions with bulged adenosine as nucleophile
RNA splicing, via transesterification reactions
Nucleobase, nucleoside, nucleotide and nucleic acid metabolic process
Nuclear mRNA splicing, via spliceosome
RNA metabolic process
Cellular macromolecule metabolic process
Immune system development
Pre-B cell differentiation
Hemopoietic or lymphoid organ development
Immature B cell differentiation
Regulation of small GTPase mediated signal transduction
Regulation of catalytic activity
Regulation of GTPase activity
Performance of drug efficacy prediction
To validate context-specific functional modules are significant features for predicting the efficacy of drugs, we compared our model with elastic net, which is efficient, widely used regularized regression technique . As can be seen in Fig. 6a, our model gives better predictive performance than elastic net for 21 out of 29 drugs and we observed a significant good performance for 11 out of 29 drugs (Anastrozole, Bortezomib, Calusterone, Dromostanolone Propionate, Erlotinib, Ethinyl estradiol, Mitotane, Nelfinavir, Pazopanib hydrochloride Y, Tamibarotene, Tamoxifen citrate) (Additional file 2) , our model yielding a concordance index greater than 0.586 (p < 0.05). Elastic net gives significant performance for one out of 29 drugs (Tamibarotene). To compare performance result, we applied one tail paid t-test for comparing concordance index with Person correlation . Our method outperforms elastic net (p < 2e-4 one tail paired t-test, for comparing concordance index; p < 0.027 for comparing Person correlation) (Additional file 3). It is shown in Fig. 6c.
In our predicted result, drug efficacy related context-specific function of Lapatinib are Function 305 and Function 66. Function 305 is related to immune system development and Function66 is related to regulation of JAK-STAT cascade and cell proliferation. Lapatinib blocks EGFR, which is a target of Lapatinib. So, it makes EGFR not to transfer signal to JAK-STAT pathway. Thereby, Lapatinib negatively regulates cell proliferation. Among the drugs we experimented, Erlotinib has same therapeutic function as Lapatinib. As we expected, context-specific functions which are related to efficacy of Erlotinib are the same with as Lapatinib.
Raloxifene targets estrogen receptor and it acts as estrogen agoinst . In our research, the context-specific function of Raloxifene is Function 501 (Additional file 4). Function 501 is related to tissue morphogenesis . One of the functions of estrogen is tissue morphogenesis . Tamoxifen, which we experimented, has same therapeutic function as Raloxifene. The Function 501 is on top4 context-specific function of Tamoxifen .
GTPase activity is the context-specific function of Gefitinib in our experiment. In cellular environment, KRAS transfers signal to downstream pathways by GTPase activity. If KRAS has mutation, it consistently activates downstream pathways and causes resistance to Gefitinib .
A clinical trial validates the efficacy of personalized medicines, but does not predict it. To develop personalized medicines, it is necessary to predict the efficacy of drugs using individual genomic information. Therefore, many groups have studied approaches to predict the efficacy of drugs, but they could not explain which biological functions are related to drug activity. The context-specific function module based approach not only predicts the efficacy of drugs but also describes drug-related biological functions. In this paper, we generated the model which predicts efficacy of drugs, using 60 cell lines from NCI 60. We expect that this model will show better performance if based on larger amount of cell line data from databases such as CCLE. The proposed approach predicts secondary drugs for resistant drugs as well as suggests personalized drugs.
Kyungrin Noh provided writing assistance.
Availability of data and materials
The datasets supporting the conclusions of this article are available in the NCI-60 Human Tumor Cell Lines Screen (https://dtp.cancer.gov/databases_tools/default.htm), KEGG (http://www.genome.jp/kegg/) and BioGRID (http://thebiogrid.org).
WH designed the method, validated results and wrote the manuscript, JC designed function vector and wrote the manuscript. MK did data pre-processing and wrote the manuscript. DL managed the research and guided the scientific discussing and editing. All authors reviewed and approved the manuscript.
Publication charges for this work was funded by the Bio-Synergy Research Project (NRF-2012M3A9C4048758) of the Ministry of Science, ICT and Future Planning through the National Research Foundation.
This article has been published as part of BMC Bioinformatics Volume 17 Supplement 6, 2016: Proceedings of the ACM Ninth International Workshop on Data and Text Mining in Biomedical Informatics. The full contents of the supplement are available online at http://bmcbioinformatics.biomedcentral.com/articles/supplements/volume-17-supplement-6.
The authors declare that they have no competing interests.
Consent for publication
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- Jiang H. Overview of gefitinib in non-small cell lung cancer: an Asian perspective. Jpn J Clin Oncol. 2009;39(3):137–50.View ArticlePubMedGoogle Scholar
- Costello JC, Heiser LM, Georgii E, Gönen M, Menden MP, Wang NJ, Bansal M, Hintsanen P, Khan SA, Mpindi J-P. A community effort to assess and improve drug sensitivity prediction algorithms. Nat Biotechnol. 2014;32(12):1202–12.Google Scholar
- Papillon-Cavanagh S, De Jay N, Hachem N, Olsen C, Bontempi G, Aerts HJ, Quackenbush J, Haibe-Kains B. Comparison and validation of genomic predictors for anticancer drug sensitivity. JAMIA. 2013;20(4):597–602.Google Scholar
- Garnett MJ, Edelman EJ, Heidorn SJ, Greenman CD, Dastur A, Lau KW, Greninger P, Thompson IR, Luo X, Soares J. Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature. 2012;483(7391):570–5.Google Scholar
- Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin AA, Kim S, Wilson CJ, Lehár J, Kryukov GV, Sonkin D. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature. 2012;483(7391):603–7.Google Scholar
- Ahmad S, Gupta S, Kumar R, Varshney GC, Raghava GP. Herceptin resistance database for understanding mechanism of resistance in breast cancer patients. Sci Rep. 2014;4:4483.PubMedPubMed CentralGoogle Scholar
- Tang J, Karhinen L, Xu T, Szwajda A, Yadav B, Wennerberg K, Aittokallio T. Target inhibition networks: predicting selective combinations of druggable targets to block cancer survival pathways. PLoS Comput Biol. 2013;9(9):e1003226.Google Scholar
- Rad R, Cadinanos J, Rad L, Varela I, Strong A, Kriegl L, Constantino-Casas F, Eser S, Hieber M, Seidler B, et al. A genetic progression model of Braf(V600E)-induced intestinal tumorigenesis reveals targets for therapeutic intervention. Cancer Cell. 2013;24(1):15–29.Google Scholar
- Ebi H, Costa C, Faber AC, Nishtala M, Kotani H, Juric D, Della Pelle P, Song Y, Yano S, Mino-Kenudson M, et al. PI3K regulates MEK/ERK signaling in breast cancer via the Rac-GEF, P-Rex1. Proc Natl Acad Sci U S A. 2013;110(52):21124–9.Google Scholar
- Bissell MJ, Labarge MA. Context, tissue plasticity, and cancer: are tumor stem cells also regulated by the microenvironment? Cancer Cell. 2005;7(1):17–23.PubMedPubMed CentralGoogle Scholar
- Zeng T, Wang DC, Wang X, Xu F, Chen L. Prediction of dynamical drug sensitivity and resistance by module network rewiring-analysis based on transcriptional profiling. Drug Resist Updat. 2014;17(3):64–76.View ArticlePubMedGoogle Scholar
- Locasale JW. Metabolic rewiring drives resistance to targeted cancer therapy. Mol Syst Biol. 2012;8:597.View ArticlePubMedPubMed CentralGoogle Scholar
- Lee MJ, Ye AS, Gardino AK, Heijink AM, Sorger PK, MacBeath G, Yaffe MB. Sequential application of anticancer drugs enhances cell death by rewiring apoptotic signaling networks. Cell. 2012;149(4):780–94.Google Scholar
- Bandyopadhyay S, Mehta M, Kuo D, Sung M-K, Chuang R, Jaehnig EJ, Bodenmiller B, Licon K, Copeland W, Shales M. Rewiring of genetic networks in response to DNA damage. Science. 2010;330(6009):1385–9.Google Scholar
- Niederst MJ, Engelman JA. Bypass mechanisms of resistance to receptor tyrosine kinase inhibition in lung cancer. Sci Signal. 2013;6(294):re6.View ArticlePubMedGoogle Scholar
- Shoemaker RH. The NCI60 human tumour cell line anticancer drug screen. Nat Rev Cancer. 2006;6(10):813–23.View ArticlePubMedGoogle Scholar
- Stark C, Breitkreutz B-J, Reguly T, Boucher L, Breitkreutz A, Tyers M. BioGRID: a general repository for interaction datasets. Nucleic Acids Res. 2006;34 suppl 1:D535–9.View ArticlePubMedGoogle Scholar
- Kanehisa M, Goto S. KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 2000;28(1):27–30.View ArticlePubMedPubMed CentralGoogle Scholar
- Matys V, Fricke E, Geffers R, Gößling E, Haubrock M, Hehl R, Hornischer K, Karas D, Kel AE, Kel-Margoulis OV. TRANSFAC®: transcriptional regulation, from patterns to profiles. Nucleic Acids Res. 2003;31(1):374–8.View ArticlePubMedPubMed CentralGoogle Scholar
- Wu G, Stein L. A network module-based method for identifying cancer prognostic signatures. Genome Biol. 2012;13(12):R112.View ArticlePubMedPubMed CentralGoogle Scholar
- Bauer-Mehren A, Bundschus M, Rautschka M, Mayer MA, Sanz F, Furlong LI. Gene-disease network analysis reveals functional modules in mendelian, complex and environmental diseases. PLoS One. 2011;6(6):e20284.View ArticlePubMedPubMed CentralGoogle Scholar
- Sharan R, Ulitsky I, Shamir R. Network-based prediction of protein function. Mol Syst Biol. 2007;3:88.View ArticlePubMedPubMed CentralGoogle Scholar
- Ji J, Zhang A, Liu C, Quan X, Liu Z. Survey: Functional module detection from protein-protein interaction networks. Knowledge and Data Engineering, IEEE Transactions on. 2014;26(2):261–77.View ArticleGoogle Scholar
- Chen BJ, Litvin O, Ungar L, Pe'er D. Context Sensitive Modeling of Cancer Drug Sensitivity. PLoS One. 2015;10(8):e0133850.View ArticlePubMedPubMed CentralGoogle Scholar
- Wang Y, Xiao J, Suzek TO, Zhang J, Wang J, Bryant SH. PubChem: a public information system for analyzing bioactivities of small molecules. Nucleic Acids Res. 2009;37 suppl 2:W623–33.View ArticlePubMedPubMed CentralGoogle Scholar
- Rey JRC, Cervino EV, Rentero ML, Crespo EC, Álvaro AO, Casillas M. Raloxifene: mechanism of action, effects on bone tissue, and applicability in clinical traumatology practice. The open orthopaedics journal. 2009;3:14.View ArticlePubMedPubMed CentralGoogle Scholar
- Heldring N, Pike A, Andersson S, Matthews J, Cheng G, Hartman J, Tujague M, Ström A, Treuter E, Warner M. Estrogen receptors: how do they signal and what are their targets. Physiol Rev. 2007;87(3):905–31.Google Scholar
- Whirl‐Carrillo M, McDonagh E, Hebert J, Gong L, Sangkuhl K, Thorn C, Altman R, Klein TE. Pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther. 2012;92(4):414–7.Google Scholar
- Chen J, Bi H, Hou J, Zhang X, Zhang C, Yue L, Wen X, Liu D, Shi H, Yuan J. Atorvastatin overcomes gefitinib resistance in KRAS mutant human non-small cell lung carcinoma cells. Cell Death Dis. 2013;4(9):e814.Google Scholar