Intravital Imaging Reveals How BRAF Inhibition Generates Drug-Tolerant Microenvironments with High Integrin β1/FAK Signaling

作者：Eishu Hirata, María Romina Girotti, Amaya Virós, Steven Hooper, Bradley Spencer‐Dene, Michiyuki Matsuda, James Larkin, Richard Marais, Erik A. Sahai · 发表于：Cancer Cell · 年份：2015 · DOI：10.1016/j.ccell.2015.03.008 · 被引用次数：598 · 研究领域：Melanoma and MAPK Pathways、Cell Adhesion Molecules Research、Cellular Mechanics and Interactions

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.