Intravital imaging reveals how BRAF inhibition generates drug-tolerant microenvironments with high integrin β1/FAK signaling
journal contributionposted on 2020-07-31, 12:51 authored by Eishu Hirata, Maria Romina Girotti, Amaya Viros, Steven Hooper, Bradley Spencer-Dene, Michiyuki Matsuda, James Larkin, Richard Marais, Erik Sahai
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.
AnimalsCell Line, TumorDrug Resistance, NeoplasmFocal Adhesion Protein-Tyrosine KinasesHumansIndolesIntegrin beta1MelanomaMiceMice, Inbred C57BLProto-Oncogene Proteins B-rafSignal TransductionSulfonamidesTumor MicroenvironmentSahaiHPBRF-ackOncology & Carcinogenesis1112 Oncology and Carcinogenesis1109 Neurosciences