title: Reconstructing targetable pathways in lung cancer by integrating diverse omics data.
abstract: Global 'multi-omics' profiling of cancer cells harbours the potential for characterizing the signalling networks associated with specific oncogenes. Here we profile the transcriptome, proteome and phosphoproteome in a panel of non-small cell lung cancer (NSCLC) cell lines in order to reconstruct targetable networks associated with KRAS dependency. We develop a two-step bioinformatics strategy addressing the challenge of integrating these disparate data sets. We first define an 'abundance-score' combining transcript, protein and phospho-protein abundances to nominate differentially abundant proteins and then use the Prize Collecting Steiner Tree algorithm to identify functional sub-networks. We identify three modules centred on KRAS and MET, LCK and PAK1 and β-Catenin. We validate activation of these proteins in KRAS-dependent (KRAS-Dep) cells and perform functional studies defining LCK as a critical gene for cell proliferation in KRAS-Dep but not KRAS-independent NSCLCs. These results suggest that LCK is a potential druggable target protein in KRAS-Dep lung cancers.
authors.affiliation: 1] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan 8109, USA [2] Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA [3] Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: O Alejandro
authors.initials: OA
authors.lastname: Balbin
authors.forename: John R
authors.initials: JR
authors.lastname: Prensner
authors.forename: Anirban
authors.initials: A
authors.lastname: Sahu
authors.forename: Anastasia
authors.initials: A
authors.lastname: Yocum
authors.forename: Sunita
authors.initials: S
authors.lastname: Shankar
authors.forename: Rohit
authors.initials: R
authors.lastname: Malik
authors.forename: Damian
authors.initials: D
authors.lastname: Fermin
authors.forename: Saravana M
authors.initials: SM
authors.lastname: Dhanasekaran
authors.forename: Benjamin
authors.initials: B
authors.lastname: Chandler
authors.forename: Dafydd
authors.initials: D
authors.lastname: Thomas
authors.forename: David G
authors.initials: DG
authors.lastname: Beer
authors.forename: Xuhong
authors.initials: X
authors.lastname: Cao
authors.forename: Alexey I
authors.initials: AI
authors.lastname: Nesvizhskii
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
mesh_terms: D000465:Algorithms; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019295:Computational Biology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D053263:Gene Regulatory Networks; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000235:genetics* / Q000378:metabolism; D058990:Molecular Targeted Therapy; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D015398:Signal Transduction; D059467:Transcriptome; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C495270:CTNNB1 protein, human; C117307:KRAS protein, human; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D051176:beta Catenin; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); C515903:PAK1 protein, human; D054462:p21-Activated Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins