Letter abstract
Nature Biotechnology 27, 77 - 83 (2008)
Published online: 21 December 2008 | doi:10.1038/nbt.1513
Bead-based profiling of tyrosine kinase phosphorylation identifies SRC as a potential target for glioblastoma therapy
Jinyan Du1,2, Paula Bernasconi1,2, Karl R Clauser1, D R Mani1, Stephen P Finn3, Rameen Beroukhim1,3, Melissa Burns1,2, Bina Julian1,4, Xiao P Peng1,4, Haley Hieronymus1,2, Rebecca L Maglathlin1, Timothy A Lewis1, Linda M Liau5, Phioanh Nghiemphu6, Ingo K Mellinghoff7, David N Louis8, Massimo Loda3, Steven A Carr1, Andrew L Kung2 & Todd R Golub1,2,4
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.
- The Broad Institute of Harvard University and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA.
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA.
- Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.
- Department of Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA.
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA.
- Human Oncology and Pathogenesis Program, Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
- Molecular Pathology Unit and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Correspondence to: Todd R Golub1,2,4 e-mail: golub@broad.mit.edu
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