TY - JOUR T1 - Kinome-centric pharmacoproteomics identifies signaling pathways underlying cellular responses to targeted cancer drugs JF - bioRxiv DO - 10.1101/849281 SP - 849281 AU - Martin Golkowski AU - Ho-Tak Lau AU - Marina Chan AU - Heidi Kenerson AU - Venkata Narayana Vidadala AU - Anna Shoemaker AU - Dustin J. Maly AU - Raymond S. Yeung AU - Taranjit S. Gujral AU - Shao-En Ong Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/11/20/849281.abstract N2 - Kinase-dependent signaling networks are frequently dysregulated in cancer, driving disease progression. While kinase inhibition has become an important therapeutic approach many cancers resist drug treatment. Therefore, we need both reliable biomarkers that predict drug responses and new targets to overcome drug resistance. Determining the kinase(s) that control cancer progression in individual cancers can pose a significant challenge. Genomics has identified important, yet limited numbers of kinase driver mutations. Transcriptomics can quantify aberrant gene expression, but it cannot measure the protein phosphorylation that regulates kinase-dependent signaling network activity. Proteomics measures protein expression and phosphorylation and, therefore, quantifies aberrant signaling network activity directly. We developed a kinome-centric pharmacoproteomics platform to study signaling pathways that determine cancer drug response. Using hepatocellular carcinoma (HCC) as our model, we determined kinome activity with kinobead/LC-MS profiling, and screened 299 kinase inhibitors for growth inhibition. Integrating kinome activity with drug responses, we obtained a comprehensive database of predictive biomarkers, and kinase targets that promote drug sensitivity and resistance. Our dataset specified pathway-based biomarkers for the clinical HCC drugs sorafenib, regorafenib and lenvatinib, and we found these biomarkers enriched in human HCC specimens. Strikingly, our database also revealed signaling pathways that promote HCC cell epithelial-mesenchymal transition (EMT) and drug resistance, and that NUAK1 and NUAK2 regulate these pathways. Inhibition of these kinases reversed the EMT and sensitized HCC cells to kinase inhibition. These results demonstrate that our kinome pharmacoproteomics platform discovers both predictive biomarkers for personalized oncology and novel cancer drug targets. ER -