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

Nat Biotechnol
Authors
Keywords
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.

Year of Publication
2009
Journal
Nat Biotechnol
Volume
27
Issue
1
Pages
77-83
Date Published
2009 Jan
ISSN
1546-1696
URL
DOI
10.1038/nbt.1513
PubMed ID
19098899
PubMed Central ID
PMC3057643
Links
Grant list
U54 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