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

Area of Science:

• Oncology
• Biochemistry
• Molecular Biology

Background:

• Aberrant tyrosine kinase activation is a key oncogenic mechanism, but many such events are currently undiscovered.
• Understanding tyrosine kinase activity is crucial for developing targeted cancer therapies.

Purpose of the Study:

• To develop a high-throughput, cost-effective method for profiling tyrosine kinase activation across various cancer types.
• To identify novel therapeutic targets by creating a tyrosine kinase-activation catalog.

Main Methods:

• A novel bead-based assay was developed to detect phosphorylation of wild-type and mutant tyrosine kinases in a multiplexed format.
• The method was applied to profile 130 human cancer cell lines to create a tyrosine kinase-activation catalog.

Main Results:

• SRC was identified as frequently phosphorylated in glioblastoma cell lines and activated in primary glioblastoma patient samples.
• The SRC inhibitor dasatinib demonstrated efficacy in inhibiting glioblastoma cell viability, migration, and tumor growth in vivo.
• Confirmation that SRC is a relevant target of dasatinib, despite its broad kinase inhibition profile.

Conclusions:

• Tyrosine kinome-wide phosphorylation profiling is feasible and provides valuable insights into cancer biology.
• SRC activation is implicated in glioblastoma, suggesting its potential as a therapeutic target for this cancer type.