LKB1 Loss induces characteristic patterns of gene expression in human tumors associated with NRF2 activation and attenuation of PI3K-AKT

J Thorac Oncol. 2014 Jun;9(6):794-804. doi: 10.1097/JTO.0000000000000173.

Abstract

Introduction: Inactivation of serine/threonine kinase 11 (STK11 or LKB1) is common in lung cancer, and understanding the pathways and phenotypes altered as a consequence will aid the development of targeted therapeutic strategies. Gene and protein expressions in a murine model of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (Kras)-mutant lung cancer have been studied to gain insight into the biology of these tumors. However, the molecular consequences of LKB1 loss in human lung cancer have not been fully characterized.

Methods: We studied gene expression profiles associated with LKB1 loss in resected lung adenocarcinomas, non-small-cell lung cancer cell lines, and murine tumors. The biological significance of dysregulated genes was interpreted using gene set enrichment and transcription factor analyses and also by integration with somatic mutations and proteomic data.

Results: Loss of LKB1 is associated with consistent gene expression changes in resected human lung cancers and cell lines that differ substantially from the mouse model. Our analysis implicates novel biological features associated with LKB1 loss, including altered mitochondrial metabolism, activation of the nuclear respiratory factor 2 (NRF2) transcription factor by kelch-like ECH-associated protein 1 (KEAP1) mutations, and attenuation of the phosphatidylinositiol 3-kinase and v-akt murine thymoma viral oncogene homolog (PI3K/AKT) pathway. Furthermore, we derived a 16-gene classifier that accurately predicts LKB1 mutations and loss by nonmutational mechanisms. In vitro, transduction of LKB1 into LKB1-mutant cell lines results in attenuation of this signature.

Conclusion: Loss of LKB1 defines a subset of lung adenocarcinomas associated with characteristic molecular phenotypes and distinctive gene expression features. Studying these effects may improve our understanding of the biology of these tumors and lead to the identification of targeted treatment strategies.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Adaptor Proteins, Signal Transducing / genetics
  • Adenocarcinoma / genetics*
  • Animals
  • Ataxia Telangiectasia Mutated Proteins / genetics
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Cell Line, Tumor
  • Cytoskeletal Proteins / genetics
  • ErbB Receptors / genetics
  • GA-Binding Protein Transcription Factor / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Kelch-Like ECH-Associated Protein 1
  • Lung Neoplasms / genetics*
  • Mice
  • Mitochondria / metabolism
  • Multigene Family
  • Mutation
  • NF-E2-Related Factor 2 / metabolism*
  • Phosphatidylinositol 3-Kinase / metabolism*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Proto-Oncogene Proteins p21(ras)
  • RNA, Messenger / metabolism
  • Signal Transduction
  • Transcriptome*
  • Tumor Suppressor Protein p53 / genetics
  • ras Proteins / genetics

Substances

  • Adaptor Proteins, Signal Transducing
  • Cytoskeletal Proteins
  • GA-Binding Protein Transcription Factor
  • Intracellular Signaling Peptides and Proteins
  • KEAP1 protein, human
  • KRAS protein, human
  • Keap1 protein, mouse
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Tumor Suppressor Protein p53
  • STK11 protein, human
  • Phosphatidylinositol 3-Kinase
  • ErbB Receptors
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • AMP-Activated Protein Kinases
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins