Proteomic analysis defines kinase taxonomies specific for subtypes of breast cancer
A large study with the Gary Johnson’s group has been published in Oncotarget. This work used a proteomics technique to assess the state of the kinome en masse in breast cancer cell lines as well as primary patient tumors. We were able to identify understudied kinases that had distinct behaviors in different subtypes as well as develop a kinome activation state “signature” that was predictive of breast cancer subtype. This took a big effort so congrats to everyone involved!
Collins KAL, Stuhlmiller T, Zawistowski JS, East MP, Pham T, Hall CR, Goulet DR, Bevill SM, Angus SP, Velarde SH, Sciaky N, Oprea TI, Graves LM, Johnson GL, Gomez SM. Proteomic analysis of the breast cancer kinome integrates understudied kinases into functional networks. Oncotarget. 2018. https://doi.org/10.18632/oncotarget.24337
Abstract: Multiplexed small molecule inhibitors covalently bound to Sepharose beads (MIBs) were used to capture functional kinases in luminal, HER2-enriched and triple negative (basal-like and claudin-low) breast cancer cell lines and tumors. Kinase MIB-binding profiles at baseline without perturbation proteomically distinguished the four breast cancer subtypes. Understudied kinases, whose disease associations and pharmacology are generally unexplored, were highly represented in MIB-binding taxonomies and are integrated into signaling subnetworks with kinases that have been previously well characterized in breast cancer. Computationally it was possible to define subtypes using profiles of less than 50 of the more than 300 kinases bound to MIBs that included understudied as well as metabolic and lipid kinases. Furthermore, analysis of MIB-binding profiles established potential functional annotations for these understudied kinases. Thus, comprehensive MIBs-based capture of kinases provides a unique proteomics-based method for integration of poorly characterized kinases of the understudied kinome into functional subnetworks in breast cancer cells and tumors that is not possible using genomic strategies. The MIB-binding profiles readily defined subtype-selective differential adaptive kinome reprogramming in response to targeted kinase inhibition, demonstrating how MIB profiles can be used in determining dynamic kinome changes that result in subtype selective phenotypic state changes.