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Nat Biotechnol DOI:10.1038/nbt.1513

Bead-based profiling of tyrosine kinase phosphorylation identifies SRC as a potential target for glioblastoma therapy.

Publication TypeJournal Article
Year of Publication2009
AuthorsDu, J, Bernasconi, P, Clauser, KR, Mani, DR, Finn, SP, Beroukhim, R, Burns, M, Julian, B, Peng, XP, Hieronymus, H, Maglathlin, RL, Lewis, TA, Liau, LM, Nghiemphu, P, Mellinghoff, IK, Louis, DN, Loda, M, Carr, SA, Kung, AL, Golub, TR
JournalNat Biotechnol
Volume27
Issue1
Pages77-83
Date Published2009 Jan
ISSN1546-1696
KeywordsAnimals, Biotechnology, Cell Line, Tumor, Dasatinib, Drug Resistance, Neoplasm, Genetic Techniques, Glioblastoma, Humans, Male, Mice, Mice, Nude, Neoplasm Transplantation, Phosphorylation, Protein-Tyrosine Kinases, Pyrimidines, src-Family Kinases, Thiazoles
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.

URLhttp://dx.doi.org/10.1038/nbt.1513
DOI10.1038/nbt.1513
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/19098899?dopt=Abstract

Alternate JournalNat. Biotechnol.
PubMed ID19098899
PubMed Central IDPMC3057643
Grant ListU54 CA112962-02 / CA / NCI NIH HHS / United States
U54 CA112962-05 / CA / NCI NIH HHS / United States
K08 CA122833-02 / CA / NCI NIH HHS / United States
U54 CA112962-01 / CA / NCI NIH HHS / United States
K08 CA122833-01A1 / CA / NCI NIH HHS / United States
K08 CA122833 / CA / NCI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
N01 CO012400 / CO / NCI NIH HHS / United States
U54 CA112962 / CA / NCI NIH HHS / United States
N01CO12400 / CA / NCI NIH HHS / United States
U54 CA112962-03 / CA / NCI NIH HHS / United States
U54 CA112962-04 / CA / NCI NIH HHS / United States
N01-CO-12400 / CO / NCI NIH HHS / United States
U54 CA112962-02S1 / CA / NCI NIH HHS / United States