Reconstructing targetable pathways in lung cancer by integrating diverse omics data

Nat Commun. 2013;4:2617. doi: 10.1038/ncomms3617.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Antineoplastic Agents / pharmacology*
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Computational Biology*
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Gene Regulatory Networks
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / genetics*
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / metabolism
  • Molecular Targeted Therapy
  • Phosphoproteins / genetics*
  • Phosphoproteins / metabolism
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-met / genetics
  • Proto-Oncogene Proteins c-met / metabolism
  • Proto-Oncogene Proteins p21(ras)
  • Signal Transduction
  • Transcriptome
  • beta Catenin / genetics
  • beta Catenin / metabolism
  • p21-Activated Kinases / genetics
  • p21-Activated Kinases / metabolism
  • ras Proteins / genetics*
  • ras Proteins / metabolism

Substances

  • Antineoplastic Agents
  • CTNNB1 protein, human
  • KRAS protein, human
  • Phosphoproteins
  • Proto-Oncogene Proteins
  • beta Catenin
  • MET protein, human
  • Proto-Oncogene Proteins c-met
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
  • PAK1 protein, human
  • p21-Activated Kinases
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins