Integrative genomic and proteomic analyses identify targets for Lkb1-deficient metastatic lung tumors.
Cancer Cell, 2010/6/15;17(6):547-59.
Carretero J[1], Shimamura T, Rikova K, Jackson AL, Wilkerson MD, Borgman CL, Buttarazzi MS, Sanofsky BA, McNamara KL, Brandstetter KA, Walton ZE, Gu TL, Silva JC, Crosby K, Shapiro GI, Maira SM, Ji H, Castrillon DH, Kim CF, García-Echeverría C, Bardeesy N, Sharpless NE, Hayes ND, Kim WY, Engelman JA, Wong KK
Affiliations
PMID: 20541700DOI: 10.1016/j.ccr.2010.04.026
Impact factor: 38.585
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.
MeSH terms
AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Animals; Carcinoma, Non-Small-Cell Lung; Cell Adhesion; Cell Line, Tumor; Cell Movement; Cell Transdifferentiation; Drug Therapy, Combination; Enzyme Inhibitors; Female; Focal Adhesion Protein-Tyrosine Kinases; Focal Adhesions; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genomics; Humans; Intracellular Signaling Peptides and Proteins; Lung Neoplasms; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Mice; Mice, Mutant Strains; Mice, Nude; Neoplasm Metastasis; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Proteomics; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); RNA Interference; Signal Transduction; TOR Serine-Threonine Kinases; Up-Regulation; Xenograft Model Antitumor Assays; ras Proteins; src-Family Kinases
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