Abstract
Glioblastoma (GBM) is the most common and malignant adult brain tumor. Five- year survival following complete resection, chemotherapy, and radiotherapy is below 10%. Despite years of research, few advancements have been made in the treatment of GBM. Targeted therapies are largely ineffective due resistance pathways, including kinome reprogramming, which involves upregulation of kinases to activate alternative survival pathways. Kinome reprogramming is thought to underlie the resistance of cancers to BRD4 inhibitors, presenting a roadblock in the treatment of GBM.
The active kinome of a panel of newly diagnosed and recurrent GBM patient- derived xenograft (PDX) tumors was measured using quantitative SILAC mass spectrometry with multiplexed inhibitor beads. Using this knowledge, we were able to make predictions of kinase inhibitors that synergize with BET inhibitors using our platform SynergySeq. The kinase targets were validated by measuring the BET-inhibitor induced kinome reprogramming in GBM PDX cells before and after treatment with a BRD4 inhibitor. We found that FGFR inhibitors were predicted to be synergistic, and the FGFR1 kinase was activated by BET inhibition. We found a significant synergistic effect of this combination therapy both in vitro and in vivo.
By profiling the kinomes of GBM tumors and integrating these results with gene expression data, it may be possible to tailor treatments of this devastating disease using synergistic combinations of existing kinase and epigenetic target inhibitors.