A predictive phosphorylation signature of lung cancer.
BACKGROUND
Aberrant activation of signaling pathways drives many of the fundamental biological processes that accompany tumor initiation and progression. Inappropriate phosphorylation of intermediates in these signaling pathways are a frequently observed molecular lesion that accompanies the undesirable activation or repression of pro- and anti-oncogenic pathways. Therefore, methods which directly query signaling pathway activation via phosphorylation assays in individual cancer biopsies are expected to provide important insights into the molecular "logic" that distinguishes cancer and normal tissue on one hand, and enables personalized intervention strategies on the other.


RESULTS
We first document the largest available set of tyrosine phosphorylation sites that are, individually, differentially phosphorylated in lung cancer, thus providing an immediate set of drug targets. Next, we develop a novel computational methodology to identify pathways whose phosphorylation activity is strongly correlated with the lung cancer phenotype. Finally, we demonstrate the feasibility of classifying lung cancers based on multi-variate phosphorylation signatures.


CONCLUSIONS
Highly predictive and biologically transparent phosphorylation signatures of lung cancer provide evidence for the existence of a robust set of phosphorylation mechanisms (captured by the signatures) present in the majority of lung cancers, and that reliably distinguish each lung cancer from normal. This approach should improve our understanding of cancer and help guide its treatment, since the phosphorylation signatures highlight proteins and pathways whose phosphorylation should be inhibited in order to prevent unregulated proliferation.
Wu
Chang-Jiun
CJ
Department of Biomedical Engineering, Boston University, Boston, Massachusetts, United States of America.
Cai
Tianxi
T
Rikova
Klarisa
K
Merberg
David
D
Kasif
Simon
S
Steffen
Martin
M
D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D008954:Models, Biological; D015999:Multivariate Analysis; D010641:Phenotype; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D015203:Reproducibility of Results; D015398:Signal Transduction; D012984:Software; D014443:Tyrosine / Q000737:chemistry
D004791:Enzyme Inhibitors; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases