Mapping phospho-catalytic dependencies of therapy-resistant tumours reveals actionable vulnerabilities

Jean-Philippe Coppé, Miki Mori, Bo Pan, Christina Yau, Denise M. Wolf, Ana Ruiz-Saenz, Diede Brunen, Anirudh Prahallad, Paulien Cornelissen-Steijger, Kristel Kemper, Christian Posch, Changjun Wang, Courtney A. Dreyer, Oscar Krijgsman, Pei Rong Evelyn Lee, Zhongzhong Chen, Daniel S. Peeper, Mark M. Moasser, René Bernards, Laura J. van ‘t Veer

Research output: Contribution to journalArticleAcademicpeer-review

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.
Original languageEnglish
Pages (from-to)778-790
JournalNature Cell Biology
Volume21
Issue number6
DOIs
Publication statusPublished - 1 Jun 2019
Externally publishedYes

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