Tumor-specific Kinase Motif Enrichment Analysis Identifies Personalized Therapeutic Cancer Targets
Pu, T.; Joughin, B. A.; Desai, P. P.; Forsythe, S. D.; Holewinski, R.; Remmert, K.; Gasmi, B.; Coleman, K.; Leach, T.; Johansen, A. M.; Russell, N.; Ma, L.; Rainey, A.; Sarvestani, A. L.; Smith, E.; Sinha, S.; Mukherjee, S.; Luberice, K.; Xiao, S.; Larrain, C.; Eade, A. V.; Friedman, L. R.; Ho, J.; Davis, J. L.; Blakely, A. M.; Kleiner, D. E.; Sadowski, S. M.; Andersson, T.; Rivero, J. D.; Yaffe, M. B.; Hernandez, J. M.
Show abstract
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are an uncommon and poorly understood malignancy with low mutational burden, lacking well-defined oncogenic drivers. GEP-NET mortality frequently results from extensive hepatic metastases. Accordingly, we interrogated phosphoproteomic data from GEP-NET liver metastases and patient-matched uninvolved liver to identify tumor-specific signaling and targetable tumor vulnerabilities using Kinase Motif Enrichment Analysis (KMEA), a new tool leveraging the recent Kinase Library compendium of the substrate motif specificity for nearly the entire human kinome. KMEA identified patient tumor-specific upregulation of mTOR or casein kinase 2 (CK2) activity that would be undiscoverable by standard personalized genomic and transcriptomic approaches. Striking concordance was observed between KMEA predictions for specific tumors, and their sensitivity to inhibitors of mTOR or CK2 using patient tumor-derived organoids. These findings reveal potential clinically-actionable protein kinases hyperactivated in GEP-NETs, and more broadly indicate a general method for personalized cancer treatment using phosphoproteomics and KMEA-derived kinase activity signatures.
Matching journals
The top 10 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Kinome Profiling of Gastrointestinal Stromal Tumors Using Multiplexed Inhibitor Beads and Mass Spectrometry Identifies Wee1 as Candidate Therapeutic Target 93%
- Drug screening in human physiologic medium identifies uric acid as an inhibitor of rigosertib efficacy 91%
- IMPDH inhibitors for anti-tumor therapy in tuberous sclerosis complex 90%
Similar papers in this journal
- XENTURION, a multidimensional resource of xenografts and tumoroids from metastatic colorectal cancer patients for population-level translational oncology 92%
- Single-Cell RNA Sequencing Reveals the Effects of Chemotherapy on Human Pancreatic Adenocarcinoma and its Tumor Microenvironment 92%
- Spatially Interacting Phosphorylation Sites and Mutations in Cancer 92%
Similar papers in this journal
- Molecular insights into early malignant transition of hepatocellular carcinoma 92%
- Genomic and transcriptomic determinants of therapy resistance and immune landscape evolution during anti-EGFR treatment in colorectal cancer 92%
- Single-cell integration and multi-modal profiling reveals phenotypes and spatial organization of neutrophils in colorectal cancer 92%
Similar papers in this journal
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.