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Updated: Jan 23, 2026

Optical Mapping of Action Potentials and Calcium Transients in the Mouse Heart
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Published on: September 13, 2011

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

Jean-Philippe Coppé1, Miki Mori2,3, Bo Pan2,4

  • 1Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA. Jean-Philippe.Coppe@ucsf.edu.

Nature Cell Biology
|June 5, 2019
PubMed

Insights

A new high-throughput system maps kinase activity in tumors to identify resistance to targeted therapies. This reveals interdependent pathways and actionable kinases for precision medicine, improving treatment strategies.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Phosphorylation networks are crucial for regulating cellular responses to therapies.
  • Mapping kinase enzymatic activity in clinical samples like tumor biopsies is technically challenging.
  • Understanding kinase dependencies is vital for developing effective cancer treatments.

Purpose of the Study:

  • To develop a practical high-throughput system for measuring kinase enzymatic activity.
  • To identify kinase dependencies in tumor biopsies and cell lines.
  • To uncover mechanisms of therapeutic resistance in BRAFV600E-driven cancers.

Main Methods:

  • Development of a 228-peptide screen to act as phospho-sensors for kinase activity.
  • Measurement of enzymatic activity for over 60 kinases, including ABLs, AKTs, CDKs, and MAPKs.
  • Application of the system to BRAFV600E-mutated colorectal cancer and melanoma specimens.

Main Results:

  • Identified targetable parallel activation of PDPK1 and PRKCA as mechanisms of intrinsic resistance to BRAFV600E-targeted therapy in colorectal cancer.
  • Discovered RPS6KB1 and PIM1 as druggable vulnerabilities in melanoma, predictive of poor outcomes in BRAFV600E patients.
  • Demonstrated that therapeutic resistance can arise from coordinated upregulation of interdependent pathways.

Conclusions:

  • The developed kinase activity-mapping system is a versatile tool for exploring actionable kinases.
  • This system aids in understanding and overcoming therapeutic resistance in precision medicine.
  • The findings highlight the potential for targeting specific kinase pathways to improve patient outcomes.

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