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Mapping phospho-catalytic dependencies of therapy-resistant tumours reveals actionable vulnerabilities
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Journal Article
Mapping phospho-catalytic dependencies of therapy-resistant tumours reveals actionable vulnerabilities
2019
Overview
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.
Coppé and colleagues design a peptide phosphorylation-screening system that simultaneously measures the enzymatic activity of multiple kinases, identifying mechanisms of therapy resistance and druggable targets in colorectal cancer and melanoma.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 3-Phosphoinositide-Dependent Protein Kinases - genetics
/ 631/67
/ 82
/ 82/47
/ 82/75
/ 96/10
/ 96/95
/ Adult
/ Aged
/ Analysis
/ Biomedical and Life Sciences
/ Colorectal Neoplasms - drug therapy
/ Colorectal Neoplasms - genetics
/ Colorectal Neoplasms - pathology
/ Drug Resistance, Neoplasm - genetics
/ Female
/ Gene Expression Regulation, Neoplastic - drug effects
/ High-throughput screening (Biochemical assaying)
/ Humans
/ Kinases
/ Male
/ MAP Kinase Signaling System - genetics
/ Mapping
/ Melanoma
/ Methods
/ Peptides
/ Phosphorylation - drug effects
/ Protein Kinase C-alpha - genetics
/ Protein Kinase Inhibitors - therapeutic use
/ Proto-Oncogene Proteins c-pim-1 - genetics
/ Sulfonamides - therapeutic use
/ Therapy
/ Tumors
