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Updated: Jun 16, 2026

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
07:49

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

Published on: July 17, 2019

Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF

Sonja J Heidorn1, Carla Milagre, Steven Whittaker

  • 1The Institute of Cancer Research, Signal Transduction Team, Section of Cell and Molecular Biology, 237 Fulham Road, London SW3 6JB, UK.

Cell
|February 10, 2010
PubMed

Insights

Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor growth. BRAF inhibitors activate this pathway, highlighting the need for tumor genotyping before treatment to predict patient response and adverse effects.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling

Background:

  • Oncogenic RAS mutations are common drivers of cancer.
  • BRAF signaling pathways are critical in cell proliferation and survival.
  • Targeted therapies inhibiting BRAF are used in cancer treatment.

Purpose of the Study:

  • To elucidate a novel mechanism of tumorigenesis involving kinase-dead BRAF and oncogenic RAS.
  • To investigate the effects of BRAF-selective inhibitors in the context of oncogenic RAS.
  • To understand the implications for clinical practice and patient stratification.

Main Methods:

  • In vitro kinase assays to assess protein interactions and signaling.
  • Cell-based assays to measure MEK-ERK pathway activation.
  • In vivo mouse models of melanoma to study tumorigenesis.

Main Results:

  • Kinase-dead BRAF, in the presence of oncogenic RAS, promotes tumorigenesis.
  • BRAF-selective inhibitors induce RAS-dependent BRAF binding to CRAF, activating the MEK-ERK pathway.
  • This pathway activation does not occur with oncogenic BRAF inhibition.
  • Kinase-dead BRAF and oncogenic RAS cooperate to induce melanoma in mice.

Conclusions:

  • A new paradigm of BRAF-mediated signaling in tumor progression is identified.
  • Understanding pathway signaling and tumor genotyping are crucial for effective BRAF-targeted therapy.
  • Genotyping can identify patients likely to respond to BRAF inhibitors and those at risk of adverse effects.

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