Group-sparse Modeling Drug-kinase Networks for Predicting Combinatorial Drug Sensitivity in Cancer Cells

Author(s): Hui Liu, Libo Luo, Zhanzhan Cheng, Jianjiang Sun, Jihong Guan, Jie Zheng*, Shuigeng Zhou*.

Journal Name: Current Bioinformatics

Volume 13 , Issue 5 , 2018

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Abstract:

Background: Due to the intrinsic compensatory mechanism and cross-talks mong cellular signaling pathways, single-target drugs often fail to inhibit the survival pathways in cancer cells. Some multi-target combination drugs have demonstrated their high sensitivities and low side effects in cancer therapies, and thus drawn intensive attentions from researchers and pharmaceutical enterprises.

Method: Although a few computational methods have been developed to infer combination drug sensitivities based on drug-kinase interactions, they either depend on the binarization of drug-kinase binding affinities, which would lead to the loss of weak drug-target inhibitions known to affect significantly the anticancer effects, or disregard the functional group structure among the kinases involved in cancer signalling pathways. In this paper, we employed a sparse linear model, uncertain group sparse representation (UGSR), to infer essential kinases governing the cellular responses to drug treatments in cancer cells, based on the massively collected drug-kinase interactions and drug sensitivity datasets over hundreds of cancer cell lines. The inferred essential kinases can be subsequently used to calculate the cancer cell sensitivities to combination drugs.

Results: The leave-one-out cross validations and two real cases show that our method achieve high performance in predict drug sensitivities of combination drugs. Moreover, a user-friendly web interface with interactive network viewer, tabular viewer and other graphical visualization plugins, has been implemented to facilitate data access and interpretation.

Keywords: Drug combination, sparse representation, group structure, drug sensitivity, cancer cells, drug-kinase.

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Article Details

VOLUME: 13
ISSUE: 5
Year: 2018
Page: [437 - 443]
Pages: 7
DOI: 10.2174/1574893613666180118104250
Price: $58

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