10779/crick.12746111.v1
Eishu Hirata
Eishu
Hirata
Maria Romina Girotti
Maria Romina
Girotti
Amaya Viros
Amaya
Viros
Steven Hooper
Steven
Hooper
Bradley Spencer-Dene
Bradley
Spencer-Dene
Michiyuki Matsuda
Michiyuki
Matsuda
James Larkin
James
Larkin
Richard Marais
Richard
Marais
Erik Sahai
Erik
Sahai
Intravital imaging reveals how BRAF inhibition generates drug-tolerant microenvironments with high integrin β1/FAK signaling
The Francis Crick Institute
2020
Animals
Cell Line, Tumor
Drug Resistance, Neoplasm
Focal Adhesion Protein-Tyrosine Kinases
Humans
Indoles
Integrin beta1
Melanoma
Mice
Mice, Inbred C57BL
Proto-Oncogene Proteins B-raf
Signal Transduction
Sulfonamides
Tumor Microenvironment
Sahai
HP
BRF-ack
Oncology & Carcinogenesis
1112 Oncology and Carcinogenesis
1109 Neurosciences
2020-07-31 12:51:53
Journal contribution
https://crick.figshare.com/articles/journal_contribution/Intravital_imaging_reveals_how_BRAF_inhibition_generates_drug-tolerant_microenvironments_with_high_integrin_1_FAK_signaling/12746111
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.