1. Mapping phospho-catalytic dependencies of therapy-resistant tumours reveals actionable vulnerabilities
- Author
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Coppé, Jean-Philippe, Mori, Miki, Pan, Bo, Yau, Christina, Wolf, Denise M, Ruiz-Saenz, Ana, Brunen, Diede, Prahallad, Anirudh, Cornelissen-Steijger, Paulien, Kemper, Kristel, Posch, Christian, Wang, Changjun, Dreyer, Courtney A, Krijgsman, Oscar, Lee, Pei Rong Evelyn, Chen, Zhongzhong, Peeper, Daniel S, Moasser, Mark M, Bernards, René, and van ‘t Veer, Laura J
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Cancer ,2.1 Biological and endogenous factors ,Aetiology ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Good Health and Well Being ,3-Phosphoinositide-Dependent Protein Kinases ,Adult ,Aged ,Cell Line ,Tumor ,Colorectal Neoplasms ,Drug Resistance ,Neoplasm ,Female ,Gene Expression Regulation ,Neoplastic ,Humans ,Indoles ,Kaplan-Meier Estimate ,MAP Kinase Signaling System ,Male ,Melanoma ,Middle Aged ,Peptides ,Phosphorylation ,Protein Kinase C-alpha ,Protein Kinase Inhibitors ,Proto-Oncogene Proteins c-pim-1 ,Sulfonamides ,Medical and Health Sciences ,Developmental Biology ,Biochemistry and cell biology - Abstract
Phosphorylation networks intimately regulate mechanisms of response to therapies. Mapping the phospho-catalytic profile of kinases in cells or tissues remains a challenge. Here, we introduce a practical high-throughput system to measure the enzymatic activity of kinases using biological peptide targets as phospho-sensors to reveal kinase dependencies in tumour biopsies and cell lines. A 228-peptide screen was developed to detect the activity of >60 kinases, including ABLs, AKTs, CDKs and MAPKs. Focusing on BRAFV600E tumours, we found mechanisms of intrinsic resistance to BRAFV600E-targeted therapy in colorectal cancer, including targetable parallel activation of PDPK1 and PRKCA. Furthermore, mapping the phospho-catalytic signatures of melanoma specimens identifies RPS6KB1 and PIM1 as emerging druggable vulnerabilities predictive of poor outcome in BRAFV600E patients. The results show that therapeutic resistance can be caused by the concerted upregulation of interdependent pathways. Our kinase activity-mapping system is a versatile strategy that innovates the exploration of actionable kinases for precision medicine.
- Published
- 2019