Quantitative chemical proteomics reveals new potential drug targets in head and neck cancer.

Zhixiang Wu; Jessica B Doondeea; Amin Moghaddas Gholami; Melanie Janning; Simone Lemeer; Karl Kramer; Suzanne A Eccles; Susanne M Gollin; Reidar Grenman; Axel Walch; Stephan M Feller; Bernhard Kuster

Quantitative chemical proteomics reveals new potential drug targets in head and neck cancer.

Standard

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, Vol. 10, No. 12, 12, 2011, p. 11635.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Wu, Z, Doondeea, JB, Gholami, AM, Janning, M, Lemeer, S, Kramer, K, Eccles, SA, Gollin, SM, Grenman, R, Walch, A, Feller, SM & Kuster, B 2011, 'Quantitative chemical proteomics reveals new potential drug targets in head and neck cancer.', MOL CELL PROTEOMICS, vol. 10, no. 12, 12, pp. 11635. <http://www.ncbi.nlm.nih.gov/pubmed/21955398?dopt=Citation>

APA

Wu, Z., Doondeea, J. B., Gholami, A. M., Janning, M., Lemeer, S., Kramer, K., Eccles, S. A., Gollin, S. M., Grenman, R., Walch, A., Feller, S. M., & Kuster, B. (2011). Quantitative chemical proteomics reveals new potential drug targets in head and neck cancer. MOL CELL PROTEOMICS, 10(12), 11635. [12]. http://www.ncbi.nlm.nih.gov/pubmed/21955398?dopt=Citation

Vancouver

Wu Z, Doondeea JB, Gholami AM, Janning M, Lemeer S, Kramer K et al. Quantitative chemical proteomics reveals new potential drug targets in head and neck cancer. MOL CELL PROTEOMICS. 2011;10(12):11635. 12.

Bibtex

@article{d324a6939d0e4dc7bb06285e4d4515ec,

title = "Quantitative chemical proteomics reveals new potential drug targets in head and neck cancer.",

abstract = "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.",

keywords = "Humans, Cell Line, Tumor, Gene Knockdown Techniques, Tissue Array Analysis, Proteomics, Protein Kinase Inhibitors/pharmacology, Molecular Targeted Therapy, RNA Interference, Receptor, Epidermal Growth Factor/metabolism, Protein-Serine-Threonine Kinases/metabolism, Cell Cycle Proteins/metabolism, Cell Survival, Nuclear Proteins/metabolism, Protein Kinases/metabolism, Carcinoma/drug therapy/*enzymology, Janus Kinase 1/metabolism, Protein-Tyrosine Kinases/metabolism, Proto-Oncogene Proteins c-met/metabolism, Receptor, EphA2/genetics/*metabolism, Receptor-Interacting Protein Serine-Threonine Kinase 2/metabolism, Tongue Neoplasms/drug therapy/*enzymology, src-Family Kinases/genetics/metabolism, Humans, Cell Line, Tumor, Gene Knockdown Techniques, Tissue Array Analysis, Proteomics, Protein Kinase Inhibitors/pharmacology, Molecular Targeted Therapy, RNA Interference, Receptor, Epidermal Growth Factor/metabolism, Protein-Serine-Threonine Kinases/metabolism, Cell Cycle Proteins/metabolism, Cell Survival, Nuclear Proteins/metabolism, Protein Kinases/metabolism, Carcinoma/drug therapy/*enzymology, Janus Kinase 1/metabolism, Protein-Tyrosine Kinases/metabolism, Proto-Oncogene Proteins c-met/metabolism, Receptor, EphA2/genetics/*metabolism, Receptor-Interacting Protein Serine-Threonine Kinase 2/metabolism, Tongue Neoplasms/drug therapy/*enzymology, src-Family Kinases/genetics/metabolism",

author = "Zhixiang Wu and Doondeea, {Jessica B} and Gholami, {Amin Moghaddas} and Melanie Janning and Simone Lemeer and Karl Kramer and Eccles, {Suzanne A} and Gollin, {Susanne M} and Reidar Grenman and Axel Walch and Feller, {Stephan M} and Bernhard Kuster",

year = "2011",

language = "English",

volume = "10",

pages = "11635",

journal = "MOL CELL PROTEOMICS",

issn = "1535-9476",

publisher = "American Society for Biochemistry and Molecular Biology Inc.",

number = "12",

}

RIS

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