Quantitative chemical proteomics reveals new potential drug targets in head and neck cancer.
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Quantitative chemical proteomics reveals new potential drug targets in head and neck cancer. / Wu, Zhixiang; Doondeea, Jessica B; Gholami, Amin Moghaddas; Janning, Melanie; Lemeer, Simone; Kramer, Karl; Eccles, Suzanne A; Gollin, Susanne M; Grenman, Reidar; Walch, Axel; Feller, Stephan M; Kuster, Bernhard.
in: MOL CELL PROTEOMICS, Jahrgang 10, Nr. 12, 12, 2011, S. 11635.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Quantitative chemical proteomics reveals new potential drug targets in head and neck cancer.
AU - Wu, Zhixiang
AU - Doondeea, Jessica B
AU - Gholami, Amin Moghaddas
AU - Janning, Melanie
AU - Lemeer, Simone
AU - Kramer, Karl
AU - Eccles, Suzanne A
AU - Gollin, Susanne M
AU - Grenman, Reidar
AU - Walch, Axel
AU - Feller, Stephan M
AU - Kuster, Bernhard
PY - 2011
Y1 - 2011
N2 - Tumors of the head and neck represent a molecularly diverse set of human cancers, but relatively few proteins have actually been shown to drive the disease at the molecular level. To identify new targets for individualized diagnosis or therapeutic intervention, we performed a kinase centric chemical proteomics screen and quantified 146 kinases across 34 head and neck squamous cell carcinoma (HNSCC) cell lines using intensity-based label-free mass spectrometry. Statistical analysis of the profiles revealed significant intercell line differences for 42 kinases (p < 0.05), and loss of function experiments using siRNA in high and low expressing cell lines identified kinases including EGFR, NEK9, LYN, JAK1, WEE1, and EPHA2 involved in cell survival and proliferation. EGFR inhibition by the small molecule inhibitors lapatinib, gefitinib, and erlotinib as well as siRNA led to strong reduction of viability in high but not low expressing lines, confirming EGFR as a drug target in 10-20% of HNSCC cell lines. Similarly, high, but not low EPHA2-expressing cells showed strongly reduced viability concomitant with down-regulation of AKT and ERK signaling following EPHA2 siRNA treatment or EPHA1-Fc ligand exposure, suggesting that EPHA2 is a novel drug target in HNSCC. This notion is underscored by immunohistochemical analyses showing that high EPHA2 expression is detected in a subset of HNSCC tissues and is associated with poor prognosis. Given that the approved pan-SRC family kinase inhibitor dasatinib is also a very potent inhibitor of EPHA2, our findings may lead to new therapeutic options for HNSCC patients. Importantly, the strategy employed in this study is generic and therefore also of more general utility for the identification of novel drug targets and molecular pathway markers in tumors. This may ultimately lead to a more rational approach to individualized cancer diagnosis and therapy.
AB - Tumors of the head and neck represent a molecularly diverse set of human cancers, but relatively few proteins have actually been shown to drive the disease at the molecular level. To identify new targets for individualized diagnosis or therapeutic intervention, we performed a kinase centric chemical proteomics screen and quantified 146 kinases across 34 head and neck squamous cell carcinoma (HNSCC) cell lines using intensity-based label-free mass spectrometry. Statistical analysis of the profiles revealed significant intercell line differences for 42 kinases (p < 0.05), and loss of function experiments using siRNA in high and low expressing cell lines identified kinases including EGFR, NEK9, LYN, JAK1, WEE1, and EPHA2 involved in cell survival and proliferation. EGFR inhibition by the small molecule inhibitors lapatinib, gefitinib, and erlotinib as well as siRNA led to strong reduction of viability in high but not low expressing lines, confirming EGFR as a drug target in 10-20% of HNSCC cell lines. Similarly, high, but not low EPHA2-expressing cells showed strongly reduced viability concomitant with down-regulation of AKT and ERK signaling following EPHA2 siRNA treatment or EPHA1-Fc ligand exposure, suggesting that EPHA2 is a novel drug target in HNSCC. This notion is underscored by immunohistochemical analyses showing that high EPHA2 expression is detected in a subset of HNSCC tissues and is associated with poor prognosis. Given that the approved pan-SRC family kinase inhibitor dasatinib is also a very potent inhibitor of EPHA2, our findings may lead to new therapeutic options for HNSCC patients. Importantly, the strategy employed in this study is generic and therefore also of more general utility for the identification of novel drug targets and molecular pathway markers in tumors. This may ultimately lead to a more rational approach to individualized cancer diagnosis and therapy.
KW - Humans
KW - Cell Line, Tumor
KW - Gene Knockdown Techniques
KW - Tissue Array Analysis
KW - Proteomics
KW - Protein Kinase Inhibitors/pharmacology
KW - Molecular Targeted Therapy
KW - RNA Interference
KW - Receptor, Epidermal Growth Factor/metabolism
KW - Protein-Serine-Threonine Kinases/metabolism
KW - Cell Cycle Proteins/metabolism
KW - Cell Survival
KW - Nuclear Proteins/metabolism
KW - Protein Kinases/metabolism
KW - Carcinoma/drug therapy/enzymology
KW - Janus Kinase 1/metabolism
KW - Protein-Tyrosine Kinases/metabolism
KW - Proto-Oncogene Proteins c-met/metabolism
KW - Receptor, EphA2/genetics/metabolism
KW - Receptor-Interacting Protein Serine-Threonine Kinase 2/metabolism
KW - Tongue Neoplasms/drug therapy/enzymology
KW - src-Family Kinases/genetics/metabolism
KW - Humans
KW - Cell Line, Tumor
KW - Gene Knockdown Techniques
KW - Tissue Array Analysis
KW - Proteomics
KW - Protein Kinase Inhibitors/pharmacology
KW - Molecular Targeted Therapy
KW - RNA Interference
KW - Receptor, Epidermal Growth Factor/metabolism
KW - Protein-Serine-Threonine Kinases/metabolism
KW - Cell Cycle Proteins/metabolism
KW - Cell Survival
KW - Nuclear Proteins/metabolism
KW - Protein Kinases/metabolism
KW - Carcinoma/drug therapy/enzymology
KW - Janus Kinase 1/metabolism
KW - Protein-Tyrosine Kinases/metabolism
KW - Proto-Oncogene Proteins c-met/metabolism
KW - Receptor, EphA2/genetics/metabolism
KW - Receptor-Interacting Protein Serine-Threonine Kinase 2/metabolism
KW - Tongue Neoplasms/drug therapy/enzymology
KW - src-Family Kinases/genetics/metabolism
M3 - SCORING: Journal article
VL - 10
SP - 11635
JO - MOL CELL PROTEOMICS
JF - MOL CELL PROTEOMICS
SN - 1535-9476
IS - 12
M1 - 12
ER -