Kinase Centric Chemical Proteomics Provides Novel Insights into Individual Cancer Biology

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SELECTBIO

Bernhard Kuster, Chair of Proteomics and Bioanalytics, Technical University Munich

Abstract
Many tumors are driven by aberrant kinase expression or activity but the molecular heterogeneity of individual tumors is significant and largely unknown. We have developed a chemical proteomics approach based on small molecule kinase inhibitor probes and quantitative mass spectrometry that enabled e.g. the profiling of 146 kinases across 34 head and neck squamous cell carcinoma (HNSCC) cell lines of the tongue. Statistical analysis revealed significant inter cell line differences for 42 kinases and loss of function experiments using siRNA identified EGFR, NEK9, LYN, JAK1, WEE1, and EPHA2 to be involved in cell survival and proliferation. EGFR and EPHA2 were validated as drug targets by a number of functional assays including small molecule drugs, siRNA and receptor ligands. Immunohistochemical analyses showed that high EPHA2 expression is detected in a HNSCC patient tissues and is associated with poor prognosis. Given that the approved drug dasatinib is a potent inhibitor of EPHA2, our findings may lead to new therapeutic options for HNSCC patients. The strategy employed in this study is of general utility for the identification of novel drug targets and molecular pathway markers in tumors which may ultimately lead to a more rational approach to individualized cancer diagnosis and therapy.