Hirata, Eishu Girotti, Maria Romina Viros, Amaya Hooper, Steven Spencer-Dene, Bradley Matsuda, Michiyuki Larkin, James Marais, Richard Sahai, Erik Intravital imaging reveals how BRAF inhibition generates drug-tolerant microenvironments with high integrin β1/FAK signaling 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. 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
    https://crick.figshare.com/articles/journal_contribution/Intravital_imaging_reveals_how_BRAF_inhibition_generates_drug-tolerant_microenvironments_with_high_integrin_1_FAK_signaling/12746111