Knowledge-guided gene prioritization reveals new insights into the mechanisms of chemoresistance

Amin Emad, Junmei Cairns, Krishna R Kalari, Liewei M Wang, Saurabh Sinha

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Background: Identification of genes whose basal mRNA expression predicts the sensitivity of tumor cells to cytotoxic treatments can play an important role in individualized cancer medicine. It enables detailed characterization of the mechanism of action of drugs. Furthermore, screening the expression of these genes in the tumor tissue may suggest the best course of chemotherapy or a combination of drugs to overcome drug resistance. Results: We developed a computational method called ProGENI to identify genes most associated with the variation of drug response across different individuals, based on gene expression data. In contrast to existing methods, ProGENI also utilizes prior knowledge of protein-protein and genetic interactions, using random walk techniques. Analysis of two relatively new and large datasets including gene expression data on hundreds of cell lines and their cytotoxic responses to a large compendium of drugs reveals a significant improvement in prediction of drug sensitivity using genes identified by ProGENI compared to other methods. Our siRNA knockdown experiments on ProGENI-identified genes confirmed the role of many new genes in sensitivity to three chemotherapy drugs: cisplatin, docetaxel, and doxorubicin. Based on such experiments and extensive literature survey, we demonstrate that about 73% of our top predicted genes modulate drug response in selected cancer cell lines. In addition, global analysis of genes associated with groups of drugs uncovered pathways of cytotoxic response shared by each group. Conclusions: Our results suggest that knowledge-guided prioritization of genes using ProGENI gives new insight into mechanisms of drug resistance and identifies genes that may be targeted to overcome this phenomenon.

Original languageEnglish (US)
Article number153
JournalGenome Biology
Volume18
Issue number1
DOIs
StatePublished - Aug 11 2017

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prioritization
drug
gene
drugs
Genes
genes
Pharmaceutical Preparations
drug resistance
chemotherapy
docetaxel
Gene Expression
Drug Resistance
gene expression
drug therapy
tumor
Neoplasms
cancer
cell lines
Drug Therapy
Cell Line

Keywords

  • Chemoresistance
  • Chemotherapy
  • Drug sensitivity
  • Gene interaction network
  • Gene prioritization
  • Network-based algorithm

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Genetics
  • Cell Biology

Cite this

Knowledge-guided gene prioritization reveals new insights into the mechanisms of chemoresistance. / Emad, Amin; Cairns, Junmei; Kalari, Krishna R; Wang, Liewei M; Sinha, Saurabh.

In: Genome Biology, Vol. 18, No. 1, 153, 11.08.2017.

Research output: Contribution to journalArticle

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