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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Algorithms
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Antineoplastic Agents / pharmacology*
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Carcinoma, Non-Small-Cell Lung / drug therapy
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Carcinoma, Non-Small-Cell Lung / genetics
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Carcinoma, Non-Small-Cell Lung / metabolism
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Carcinoma, Non-Small-Cell Lung / pathology
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Cell Line, Tumor
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Computational Biology*
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Gene Expression Regulation, Neoplastic / drug effects*
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Gene Regulatory Networks
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Humans
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Lung Neoplasms / drug therapy
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / genetics*
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / metabolism
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Molecular Targeted Therapy
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Phosphoproteins / genetics*
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Phosphoproteins / metabolism
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Proto-Oncogene Proteins / genetics*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-met / genetics
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Proto-Oncogene Proteins c-met / metabolism
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Proto-Oncogene Proteins p21(ras)
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Signal Transduction
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Transcriptome
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beta Catenin / genetics
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beta Catenin / metabolism
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p21-Activated Kinases / genetics
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p21-Activated Kinases / metabolism
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ras Proteins / genetics*
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ras Proteins / metabolism
Substances
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Antineoplastic Agents
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CTNNB1 protein, human
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KRAS protein, human
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Phosphoproteins
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Proto-Oncogene Proteins
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beta Catenin
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MET protein, human
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Proto-Oncogene Proteins c-met
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
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PAK1 protein, human
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p21-Activated Kinases
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Proto-Oncogene Proteins p21(ras)
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ras Proteins