Abstract
In mice, Lkb1 deletion and activation of Kras(G12D) results in lung tumors with a high penetrance of lymph node and distant metastases. We analyzed these primary and metastatic de novo lung cancers with integrated genomic and proteomic profiles, and have identified gene and phosphoprotein signatures associated with Lkb1 loss and progression to invasive and metastatic lung tumors. These studies revealed that SRC is activated in Lkb1-deficient primary and metastatic lung tumors, and that the combined inhibition of SRC, PI3K, and MEK1/2 resulted in synergistic tumor regression. These studies demonstrate that integrated genomic and proteomic analyses can be used to identify signaling pathways that may be targeted for treatment.
Copyright 2010 Elsevier Inc. All rights reserved.
Publication types
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
MeSH terms
- AMP-Activated Protein Kinase Kinases
- AMP-Activated Protein Kinases
- Animals
- Carcinoma, Non-Small-Cell Lung / genetics
- Carcinoma, Non-Small-Cell Lung / metabolism
- Cell Adhesion / genetics
- Cell Line, Tumor
- Cell Movement / genetics
- Cell Transdifferentiation / genetics
- Drug Therapy, Combination
- Enzyme Inhibitors / therapeutic use
- Female
- Focal Adhesion Protein-Tyrosine Kinases / antagonists & inhibitors
- Focal Adhesion Protein-Tyrosine Kinases / genetics
- Focal Adhesion Protein-Tyrosine Kinases / metabolism
- Focal Adhesions / genetics
- Focal Adhesions / metabolism
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic / genetics
- Genomics*
- Humans
- Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
- Lung Neoplasms / drug therapy*
- Lung Neoplasms / genetics
- Lung Neoplasms / metabolism*
- Lung Neoplasms / pathology
- MAP Kinase Kinase 1 / antagonists & inhibitors
- MAP Kinase Kinase 2 / antagonists & inhibitors
- Mice
- Mice, Mutant Strains
- Mice, Nude
- Neoplasm Metastasis / drug therapy*
- Neoplasm Metastasis / genetics
- Phosphoinositide-3 Kinase Inhibitors
- Phosphorylation / genetics
- Protein Kinase Inhibitors / pharmacology
- Protein Kinase Inhibitors / therapeutic use
- Protein Serine-Threonine Kinases / antagonists & inhibitors
- Protein Serine-Threonine Kinases / deficiency*
- Protein Serine-Threonine Kinases / genetics
- Protein-Tyrosine Kinases / antagonists & inhibitors
- Protein-Tyrosine Kinases / genetics
- Protein-Tyrosine Kinases / metabolism
- Proteomics*
- Proto-Oncogene Proteins / genetics
- Proto-Oncogene Proteins p21(ras) / genetics
- RNA Interference
- Signal Transduction / drug effects*
- Signal Transduction / genetics
- TOR Serine-Threonine Kinases
- Up-Regulation / genetics
- Xenograft Model Antitumor Assays
- ras Proteins / genetics
- src-Family Kinases / antagonists & inhibitors
- src-Family Kinases / genetics
- src-Family Kinases / metabolism
Substances
- Enzyme Inhibitors
- Intracellular Signaling Peptides and Proteins
- KRAS protein, human
- Phosphoinositide-3 Kinase Inhibitors
- Protein Kinase Inhibitors
- Proto-Oncogene Proteins
- MTOR protein, human
- mTOR protein, mouse
- Protein-Tyrosine Kinases
- Focal Adhesion Protein-Tyrosine Kinases
- src-Family Kinases
- Protein Serine-Threonine Kinases
- STK11 protein, human
- Stk11 protein, mouse
- TOR Serine-Threonine Kinases
- AMP-Activated Protein Kinase Kinases
- AMP-Activated Protein Kinases
- MAP Kinase Kinase 1
- MAP Kinase Kinase 2
- Hras protein, mouse
- Proto-Oncogene Proteins p21(ras)
- ras Proteins