Intravital Imaging Reveals How BRAF Inhibition Generates Drug-Tolerant Microenvironments With High Integrin β1/FAK Signaling

Cancer Cell. 2015 Apr 13;27(4):574-88. doi: 10.1016/j.ccell.2015.03.008.

Abstract

Intravital imaging of BRAF-mutant melanoma cells containing an ERK/MAPK biosensor reveals how the tumor microenvironment affects response to BRAF inhibition by PLX4720. Initially, melanoma cells respond to PLX4720, but rapid reactivation of ERK/MAPK is observed in areas of high stromal density. This is linked to "paradoxical" activation of melanoma-associated fibroblasts by PLX4720 and the promotion of matrix production and remodeling leading to elevated integrin β1/FAK/Src signaling in melanoma cells. Fibronectin-rich matrices with 3-12 kPa elastic modulus are sufficient to provide PLX4720 tolerance. Co-inhibition of BRAF and FAK abolished ERK reactivation and led to more effective control of BRAF-mutant melanoma. We propose that paradoxically activated MAFs provide a "safe haven" for melanoma cells to tolerate BRAF inhibition.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm*
  • Focal Adhesion Protein-Tyrosine Kinases / metabolism*
  • Humans
  • Indoles / pharmacology
  • Indoles / therapeutic use
  • Integrin beta1 / metabolism*
  • Melanoma / drug therapy
  • Melanoma / genetics
  • Melanoma / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
  • Proto-Oncogene Proteins B-raf / genetics
  • Signal Transduction / drug effects
  • Sulfonamides / pharmacology
  • Sulfonamides / therapeutic use
  • Tumor Microenvironment*

Substances

  • Indoles
  • Integrin beta1
  • PLX 4720
  • Sulfonamides
  • Focal Adhesion Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins B-raf

Associated data

  • GEO/GSE63160