title: Intravital imaging reveals how BRAF inhibition generates drug-tolerant microenvironments with high integrin β1/FAK signaling.
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.
authors: Tumor Cell Biology Laboratory, Cancer Research UK London Research Institute, London WC2A 3LY, UK.
authors: Eishu
authors: E
authors: Hirata
authors: Molecular Oncology Group, Cancer Research UK Manchester Institute, Wilmslow Road, Manchester M20 4BX, UK.
authors: Maria Romina
authors: MR
authors: Girotti
authors: Molecular Oncology Group, Cancer Research UK Manchester Institute, Wilmslow Road, Manchester M20 4BX, UK.
authors: Amaya
authors: A
authors: Viros
authors: Tumor Cell Biology Laboratory, Cancer Research UK London Research Institute, London WC2A 3LY, UK.
authors: Steven
authors: S
authors: Hooper
authors: Experimental Histopathology Laboratory, Cancer Research UK London Research Institute, London WC2A 3LY, UK.
authors: Bradley
authors: B
authors: Spencer-Dene
authors: Laboratory of Bioimaging and Cell Signalling, Kyoto University Graduate School of Biostudies, Kyoto 606-8315, Japan.
authors: Michiyuki
authors: M
authors: Matsuda
authors: Department of Medical Oncology, Royal Marsden NHS Trust, Fulham Road, London SW3 6JJ, UK.
authors: James
authors: J
authors: Larkin
authors: Molecular Oncology Group, Cancer Research UK Manchester Institute, Wilmslow Road, Manchester M20 4BX, UK.
authors: Richard
authors: R
authors: Marais
authors: Tumor Cell Biology Laboratory, Cancer Research UK London Research Institute, London WC2A 3LY, UK. Electronic address: erik.sahai@crick.ac.uk.
authors: Erik
authors: E
authors: Sahai
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D019012:Integrin beta1 / Q000378:metabolism*; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D059016:Tumor Microenvironment
chemical_list: D007211:Indoles; D019012:Integrin beta1; C528407:PLX 4720; D013449:Sulfonamides; D051416:Focal Adhesion Protein-Tyrosine Kinases; D048493:Proto-Oncogene Proteins B-raf