title: Cancer network activity associated with therapeutic response and synergism.
abstract: Cancer patients often show no or only modest benefit from a given therapy. This major problem in oncology is generally attributed to the lack of specific predictive biomarkers, yet a global measure of cancer cell activity may support a comprehensive mechanistic understanding of therapy efficacy. We reasoned that network analysis of omic data could help to achieve this goal.
  
  
  
  A measure of "cancer network activity" (CNA) was implemented based on a previously defined network feature of communicability. The network nodes and edges corresponded to human proteins and experimentally identified interactions, respectively. The edges were weighted proportionally to the expression of the genes encoding for the corresponding proteins and relative to the number of direct interactors. The gene expression data corresponded to the basal conditions of 595 human cancer cell lines. Therapeutic responses corresponded to the impairment of cell viability measured by the half maximal inhibitory concentration (IC50) of 130 drugs approved or under clinical development. Gene ontology, signaling pathway, and transcription factor-binding annotations were taken from public repositories. Predicted synergies were assessed by determining the viability of four breast cancer cell lines and by applying two different analytical methods.
  
  
  
  The effects of drug classes were associated with CNAs formed by different cell lines. CNAs also differentiate target families and effector pathways. Proteins that occupy a central position in the network largely contribute to CNA. Known key cancer-associated biological processes, signaling pathways, and master regulators also contribute to CNA. Moreover, the major cancer drivers frequently mediate CNA and therapeutic differences. Cell-based assays centered on these differences and using uncorrelated drug effects reveals novel synergistic combinations for the treatment of breast cancer dependent on PI3K-mTOR signaling.
  
  
  
  Cancer therapeutic responses can be predicted on the basis of a systems-level analysis of molecular interactions and gene expression. Fundamental cancer processes, pathways, and drivers contribute to this feature, which can also be exploited to predict precise synergistic drug combinations.
authors.affiliation: Breast Cancer and Systems Biology Lab, Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), Gran via 199, L'Hospitalet del Llobregat, Barcelona, 08908, Catalonia, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Serra-Musach
authors.affiliation: Breast Cancer and Systems Biology Lab, Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), Gran via 199, L'Hospitalet del Llobregat, Barcelona, 08908, Catalonia, Spain.
authors.forename: Francesca
authors.initials: F
authors.lastname: Mateo
authors.affiliation: Joint IRB-BSC-CRG Program in Computational Biology, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, Barcelona, 08028, Catalonia, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Capdevila-Busquets
authors.affiliation: Breast Cancer and Systems Biology Lab, Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), Gran via 199, L'Hospitalet del Llobregat, Barcelona, 08908, Catalonia, Spain.
authors.forename: Gorka Ruiz
authors.initials: GR
authors.lastname: de Garibay
authors.affiliation: Division of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, 9800 Medical Center Dr. Rockville, Bethesda, MD, 20850, USA.
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Division of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, 9800 Medical Center Dr. Rockville, Bethesda, MD, 20850, USA.
authors.forename: Raj
authors.initials: R
authors.lastname: Guha
authors.affiliation: Division of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, 9800 Medical Center Dr. Rockville, Bethesda, MD, 20850, USA.
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Thomas
authors.affiliation: Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology (VHIO), Cellex Center, Natzaret 115-117, Barcelona, 08035, Catalonia, Spain.
authors.forename: Judit
authors.initials: J
authors.lastname: Grueso
authors.affiliation: Breast Cancer and Systems Biology Lab, Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), Gran via 199, L'Hospitalet del Llobregat, Barcelona, 08908, Catalonia, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Villanueva
authors.affiliation: Joint IRB-BSC-CRG Program in Computational Biology, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, Barcelona, 08028, Catalonia, Spain.
authors.forename: Samira
authors.initials: S
authors.lastname: Jaeger
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), IDIBELL, Gran via 199, L'Hospitalet del Llobregat, Barcelona, 08908, Catalonia, Spain.
authors.forename: Holger
authors.initials: H
authors.lastname: Heyn
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), IDIBELL, Gran via 199, L'Hospitalet del Llobregat, Barcelona, 08908, Catalonia, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Vizoso
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), IDIBELL, Gran via 199, L'Hospitalet del Llobregat, Barcelona, 08908, Catalonia, Spain.
authors.forename: Hector
authors.initials: H
authors.lastname: Pérez
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), IDIBELL, Gran via 199, L'Hospitalet del Llobregat, Barcelona, 08908, Catalonia, Spain.
authors.forename: Alex
authors.initials: A
authors.lastname: Cordero
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), IDIBELL, Gran via 199, L'Hospitalet del Llobregat, Barcelona, 08908, Catalonia, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Gonzalez-Suarez
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), IDIBELL, Gran via 199, L'Hospitalet del Llobregat, Barcelona, 08908, Catalonia, Spain.|Department of Physiological Sciences II, School of Medicine, University of Barcelona, Feixa Llarga s/n, L'Hospitalet del Llobregat, Barcelona, 08908, Catalonia, Spain.|Catalan Institution for Research and Advanced Studies (ICREA), Passeig Lluís Companys 23, Barcelona, 08010, Catalonia, Spain.
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
authors.affiliation: Department of Biochemistry, Autonomous University of Madrid (UAM), Biomedical Research Institute "Alberto Sols" (Spanish National Research Council (CSIC)-UAM), Hospital La Paz Institute for Health Research (IdiPAZ), Arzobispo Morcillo 4, Madrid, 28029, Spain.|MD Anderson International Foundation, Arturo Soria 270, Madrid, 28033, Spain.
authors.forename: Gema
authors.initials: G
authors.lastname: Moreno-Bueno
authors.affiliation: The Centre for Individualized Medicine, Department of Clinical and Experimental Medicine, Linköping University, Linköping, 58183, Sweden.
authors.forename: Andreas
authors.initials: A
authors.lastname: Tjärnberg
authors.affiliation: Hereditary Cancer Program, ICO, IDIBELL, Gran via 199, L'Hospitalet del Llobregat, Barcelona, 08908, Catalonia, Spain.
authors.forename: Conxi
authors.initials: C
authors.lastname: Lázaro
authors.affiliation: Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology (VHIO), Cellex Center, Natzaret 115-117, Barcelona, 08035, Catalonia, Spain.
authors.forename: Violeta
authors.initials: V
authors.lastname: Serra
authors.affiliation: Catalan Institution for Research and Advanced Studies (ICREA), Passeig Lluís Companys 23, Barcelona, 08010, Catalonia, Spain.|Preclinical Research Program, VHIO, Cellex Center, Natzaret 115-117, Barcelona, 08035, Catalonia, Spain.|Department of Biochemistry and Molecular Biology, Medical School Building M, Autonomous University of Barcelona, Bellaterra, 08193, Catalonia, Spain.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Arribas
authors.affiliation: The Centre for Individualized Medicine, Department of Clinical and Experimental Medicine, Linköping University, Linköping, 58183, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Benson
authors.affiliation: The Centre for Individualized Medicine, Department of Clinical and Experimental Medicine, Linköping University, Linköping, 58183, Sweden.
authors.forename: Mika
authors.initials: M
authors.lastname: Gustafsson
authors.affiliation: Division of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, 9800 Medical Center Dr. Rockville, Bethesda, MD, 20850, USA. marc.ferrer@nih.gov.
authors.forename: Marc
authors.initials: M
authors.lastname: Ferrer
authors.affiliation: Joint IRB-BSC-CRG Program in Computational Biology, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, Barcelona, 08028, Catalonia, Spain. paloy@irbbarcelona.org.|Catalan Institution for Research and Advanced Studies (ICREA), Passeig Lluís Companys 23, Barcelona, 08010, Catalonia, Spain. paloy@irbbarcelona.org.
authors.forename: Patrick
authors.initials: P
authors.lastname: Aloy
authors.affiliation: Breast Cancer and Systems Biology Lab, Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), Gran via 199, L'Hospitalet del Llobregat, Barcelona, 08908, Catalonia, Spain. mapujana@iconcologia.net.
authors.forename: Miquel Àngel
authors.initials: MÀ
authors.lastname: Pujana
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D015507:Drugs, Investigational / Q000494:pharmacology*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D063990:Gene Ontology; D053263:Gene Regulatory Networks / Q000187:drug effects*; D006801:Humans; D058977:Molecular Sequence Annotation; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D055553:Prescription Drugs / Q000494:pharmacology*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D015507:Drugs, Investigational; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D055553:Prescription Drugs; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human
keywords: Cancer; Network; Synergy; Therapy