Linking drug target and pathway activation for effective therapy using multi-task learning

Scientific Reports
Mi YangJulio Saez-Rodriguez

Abstract

Despite the abundance of large-scale molecular and drug-response data, the insights gained about the mechanisms underlying treatment efficacy in cancer has been in general limited. Machine learning algorithms applied to those datasets most often are used to provide predictions without interpretation, or reveal single drug-gene association and fail to derive robust insights. We propose to use Macau, a bayesian multitask multi-relational algorithm to generalize from individual drugs and genes and explore the interactions between the drug targets and signaling pathways' activation. A typical insight would be: "Activation of pathway Y will confer sensitivity to any drug targeting protein X". We applied our methodology to the Genomics of Drug Sensitivity in Cancer (GDSC) screening, using gene expression of 990 cancer cell lines, activity scores of 11 signaling pathways derived from the tool PROGENy as cell line input and 228 nominal targets for 265 drugs as drug input. These interactions can guide a tissue-specific combination treatment strategy, for example suggesting to modulate a certain pathway to maximize the drug response for a given tissue. We confirmed in literature drug combination strategies derived from our result for bra...Continue Reading

References

May 11, 2010·Biochemical Pharmacology·Gajanan S InamdarGavin P Robertson
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Jun 27, 2015·BMC Medical Genomics·Akram AlyassDavid Meyre
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Citations

Jan 18, 2020·Briefings in Bioinformatics·Maryam BagherianKayvan Najarian
Oct 28, 2019·Omics : a Journal of Integrative Biology·Maria KorominaGeorge P Patrinos
Jan 14, 2020·Briefings in Bioinformatics·Jinyu Chen, Louxin Zhang
Jun 4, 2020·NPJ Systems Biology and Applications·Mi YangJulio Saez-Rodriguez
Jan 31, 2020·Frontiers in Neuroscience·Yu XieXiaolong Fan
Feb 6, 2021·Scientific Reports·Yi-Ching Tang, Assaf Gottlieb
Dec 9, 2020·Drug Discovery Today·Moe ElbadawiAbdul W Basit
Apr 4, 2021·International Journal of Molecular Sciences·Noam AuslanderEugene V Koonin
Jun 18, 2021·Cell Systems·Yuge JiFabian J Theis
Oct 17, 2019·Molecular Pharmaceutics·Matteo ManicaMaría Rodríguez Martínez
Mar 26, 2019·Journal of Chemical Information and Modeling·Ulf Norinder, Fredrik Svensson
Sep 17, 2021·Briefings in Bioinformatics·Yurui Chen, Louxin Zhang
Sep 28, 2021·Briefings in Bioinformatics·Xin AnYuanfang Guan
Oct 8, 2021·Briefings in Bioinformatics·Farzaneh FiroozbakhtBenno Schwikowski

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Software Mentioned

ChEMBL
Reactome
PARADIGM
Ridge
Elastic net
Random Forest
GEX
Ontology
Forest
Random

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