Bead-based profiling of tyrosine kinase phosphorylation identifies SRC as a potential target for glioblastoma therapy Journal Article
| Authors: | Du, J.; Bernasconi, P.; Clauser, K. R.; Mani, D. R.; Finn, S. P.; Beroukhim, R.; Burns, M.; Julian, B.; Peng, X. P.; Hieronymus, H.; Maglathlin, R. L.; Lewis, T. A.; Liau, L. M.; Nghiemphu, P.; Mellinghoff, I. K.; Louis, D. N.; Loda, M.; Carr, S. A.; Kung, A. L.; Golub, T. R. |
| Article Title: | Bead-based profiling of tyrosine kinase phosphorylation identifies SRC as a potential target for glioblastoma therapy |
| Abstract: | The aberrant activation of tyrosine kinases represents an important oncogenic mechanism, and yet the majority of such events remain undiscovered. Here we describe a bead-based method for detecting phosphorylation of both wild-type and mutant tyrosine kinases in a multiplexed, high-throughput and low-cost manner. With the aim of establishing a tyrosine kinase-activation catalog, we used this method to profile 130 human cancer lines. Follow-up experiments on the finding that SRC is frequently phosphorylated in glioblastoma cell lines showed that SRC is also activated in primary glioblastoma patient samples and that the SRC inhibitor dasatinib (Sprycel) inhibits viability and cell migration in vitro and tumor growth in vivo. Testing of dasatinib-resistant tyrosine kinase alleles confirmed that SRC is indeed the relevant target of dasatinib, which inhibits many tyrosine kinases. These studies establish the feasibility of tyrosine kinome-wide phosphorylation profiling and point to SRC as a possible therapeutic target in glioblastoma. © 2009 Nature America, Inc. All rights reserved. |
| Keywords: | controlled study; human cell; nonhuman; follow up; mouse; cytology; animals; mice; cell viability; imatinib; enzyme inhibition; cell growth; protein targeting; animal experiment; animal model; cancer cell culture; high throughput screening; drug resistance, neoplasm; cell line, tumor; dasatinib; protein tyrosine kinase; pyrimidines; phosphorylation; biotechnology; wild type; enzyme phosphorylation; cell culture; mice, nude; targets; glioblastoma; wild types; cell migration; in-vivo; protein-tyrosine kinases; neoplasm transplantation; amino acids; tumor growth; cell migrations; glioblastoma cells; high throughputs; human cancers; in-vitro; relevant targets; therapeutic targets; tumor growths; tyrosine kinase; chemical reactions; steroid receptor coactivator 1; genetic techniques; src-family kinases; thiazoles |
| Journal Title: | Nature Biotechnology |
| Volume: | 27 |
| Issue: | 1 |
| ISSN: | 1087-0156 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2009-01-25 |
| Start Page: | 77 |
| End Page: | 83 |
| Language: | English |
| DOI: | 10.1038/nbt.1513 |
| PUBMED: | 19098899 |
| PROVIDER: | scopus |
| PMCID: | PMC3057643 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 34" - "Export Date: 30 November 2010" - "CODEN: NABIF" - "Source: Scopus" |
