Journal
NATURE CELL BIOLOGY
Volume 21, Issue 6, Pages 778-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41556-019-0328-z
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Funding
- US National Institute of Health [NIH U54CA209891, NIH TR000005 T1, NIH R01CA122216]
- Give Breast Cancer The Boot programme
- Friends for an Earlier Breast Cancer Test programme
- Tri-Valley SOCKs
- Natural Science Foundation of China [81001183]
- Dutch Cancer Society (KWF) [NKI-2013-5799]
- Breast Cancer Research Foundation
- Angela and Shu Kai Chan Endowed Chair
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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(V600E) tumours, we found mechanisms of intrinsic resistance to BRAF(V600E)-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(V600E) 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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