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| Nature cell biology. 2019 Jun 3. doi: 10.1038/s41556-019-0328-z. pii: 10.1038/s41556-019-0328-z |
| Mapping phospho-catalytic dependencies of therapy-resistant tumours reveals actionable vulnerabilities. |
| Coppé JP1, Mori M2, Pan B3, Yau C4, Wolf DM5, Ruiz-Saenz A6, Brunen D7, Prahallad A8, Cornelissen-Steijger P9, Kemper K10, Posch C11, Wang C12, Dreyer CA13, Krijgsman O14, Lee PRE15, Chen Z16, Peeper DS17, Moasser MM18, Bernards R19, van 't Veer LJ20 |
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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 BRAF tumours, we found mechanisms of intrinsic resistance to BRAF-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 BRAF 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. |
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Publikations ID: 31160710 Quelle: öffnen |
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