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BRAF inhibitors promote intermediate BRAF(V600E) conformations and binary interactions with activated RAS

Ruth Röck1, Johanna E Mayrhofer1, Omar Torres-Quesada1

  • 1Institute of Biochemistry and Center for Molecular Biosciences, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.

Science Advances
|August 28, 2019
PubMed

Insights

Oncogenic BRAF mutations drive cancer by altering RAF signaling. BRAF inhibitors unexpectedly stabilize inactive conformations, enhancing RAS interactions and potentially promoting drug resistance.

Area of Science:

  • Molecular biology
  • Cancer research
  • Biochemistry

Background:

  • Oncogenic BRAF mutations are key drivers of tumor formation.
  • These mutations activate the RAF-MEK-ERK signaling pathway, promoting cell proliferation.
  • Understanding BRAF conformational changes and interactions is crucial for targeted therapy.

Purpose of the Study:

  • To systematically track full-length BRAF conformations and interactions.
  • To investigate the effects of tumorigenic mutations and RAS GTP loading on BRAF.
  • To analyze the specificity and efficacy of BRAF inhibitors (BRAFi).

Main Methods:

  • Engineered luciferase-based biosensors to monitor BRAF.
  • Studied BRAF conformation shifts upon BRAFi binding.
  • Investigated RAS:RAF interactions and nanoclustering in melanoma cells.

Main Results:

  • Structurally diverse BRAFi shifted BRAF reporters between open and closed conformations.
  • BRAFi binding to V600E-mutated BRAF stabilized an inactive conformation.
  • This stabilization enhanced binary RAS:RAF interactions, independent of RAF dimerization.

Conclusions:

  • BRAFi can induce previously unappreciated allosteric effects on mutated BRAF.
  • Interference with RAS interactions antagonizes drug-induced RAS:RAF tetramer formation.
  • These findings suggest mechanisms for paradoxical kinase activation and drug resistance.

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