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

Intravital imaging reveals how BRAF inhibition generates drug-tolerant microenvironments with high integrin β1/FAK signaling.

Author information

1
Tumor Cell Biology Laboratory, Cancer Research UK London Research Institute, London WC2A 3LY, UK.
2
Molecular Oncology Group, Cancer Research UK Manchester Institute, Wilmslow Road, Manchester M20 4BX, UK.
3
Experimental Histopathology Laboratory, Cancer Research UK London Research Institute, London WC2A 3LY, UK.
4
Laboratory of Bioimaging and Cell Signalling, Kyoto University Graduate School of Biostudies, Kyoto 606-8315, Japan.
5
Department of Medical Oncology, Royal Marsden NHS Trust, Fulham Road, London SW3 6JJ, UK.
6
Tumor Cell Biology Laboratory, Cancer Research UK London Research Institute, London WC2A 3LY, UK. Electronic address: erik.sahai@crick.ac.uk.

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.

PMID:
25873177
PMCID:
PMC4402404
DOI:
10.1016/j.ccell.2015.03.008
[Indexed for MEDLINE]
Free PMC Article

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