In silico drug combination discovery for personalized cancer therapy

Minji Jeon, Sunkyu Kim, Sungjoon Park, Heewon Lee, Jaewoo Kang

Research output: Contribution to journalArticlepeer-review

42 Citations (Scopus)


Background: Drug combination therapy, which is considered as an alternative to single drug therapy, can potentially reduce resistance and toxicity, and have synergistic efficacy. As drug combination therapies are widely used in the clinic for hypertension, asthma, and AIDS, they have also been proposed for the treatment of cancer. However, it is difficult to select and experimentally evaluate effective combinations because not only is the number of cancer drug combinations extremely large but also the effectiveness of drug combinations varies depending on the genetic variation of cancer patients. A computational approach that prioritizes the best drug combinations considering the genetic information of a cancer patient is necessary to reduce the search space. Results: We propose an in-silico method for personalized drug combination therapy discovery. We predict the synergy between two drugs and a cell line using genomic information, targets of drugs, and pharmacological information. We calculate and predict the synergy scores of 583 drug combinations for 31 cancer cell lines. For feature dimension reduction, we select the mutations or expression levels of the genes in cancer-related pathways. We also used various machine learning models. Extremely Randomized Trees (ERT), a tree-based ensemble model, achieved the best performance in the synergy score prediction regression task. The correlation coefficient between the synergy scores predicted by ERT and the actual observations is 0.738. To compare with an existing drug combination synergy classification model, we reformulate the problem as a binary classification problem by thresholding the synergy scores. ERT achieved an F1 score of 0.954 when synergy scores of 20 and -20 were used as the threshold, which is 8.7% higher than that obtained by the state-of-the-art baseline model. Moreover, the model correctly predicts the most synergistic combination, from approximately 100 candidate drug combinations, as the top choice for 15 out of the 31 cell lines. For 28 out of the 31 cell lines, the model predicts the most synergistic combination in the top 10 of approximately 100 candidate drug combinations. Finally, we analyze the results, generate synergistic rules using the features, and validate the rules through the literature survey. Conclusion: Using various types of genomic information of cancer cell lines, targets of drugs, and pharmacological information, a drug combination synergy prediction pipeline is proposed. The pipeline regresses the synergy level between two drugs and a cell line as well as classifies if there exists synergy or antagonism between them. Discovering new drug combinations by our pipeline may improve personalized cancer therapy.

Original languageEnglish
Article number16
JournalBMC Systems Biology
Publication statusPublished - 2018 Mar 19

Bibliographical note

Funding Information:
Publication of this article was funded by the National Research Foundation of Korea (NRF-2016M3A9A7916996, NRF-2014M3C9A3063543 and NRF-2014R1A2A1A10051238).

Publisher Copyright:
© 2018 The Author(s).


  • Combination therapy
  • In silico
  • Synergy prediction

ASJC Scopus subject areas

  • Structural Biology
  • Modelling and Simulation
  • Molecular Biology
  • Computer Science Applications
  • Applied Mathematics


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