Abstract
BackgroundAberrant 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.ResultsWe 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.ConclusionsHighly 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.
Highlights
At the molecular level, cancers are heterogeneous diseases, arising from genetic factors, environmental carcinogens and random, somatic mutation [1]
EGFR is a receptor tyrosine kinase implicated in lung cancer and is involved in multiple biological processes, including apoptosis, cell adhesion, and growth [15,16,17]
Mutations of EGFR are seen in a set of non-small cell lung cancer (NSCLC) patients with good response to EGFR inhibitor [18,19]
Summary
Cancers are heterogeneous diseases, arising from genetic factors, environmental carcinogens and random, somatic mutation [1]. Aberrant phosphorylation status of key residues (its presence or absence) has been observed and documented in many studies, which include the original oncogene, src [4], and many others [5]. Signatures based on protein levels are starting to be developed [6]. Methods for high-throughput detection of phosphorylated residues using mass spectrometry are being rapidly developed [7,8,9,10] and applied to the study of signaling pathways [11] along with complementary analysis and modeling approaches [12,13]. Aberrant activation of signaling pathways drives many of the fundamental biological processes that accompany tumor initiation and progression. 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
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.