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

被引：497

作者：

Hirata, Eishu ^{[1
]}

Girotti, Maria Romina ^{[2
]}

Viros, Amaya ^{[2
]}

Hooper, Steven ^{[1
]}

Spencer-Dene, Bradley ^{[3
]}

Matsuda, Michiyuki ^{[4
]}

Larkin, James ^{[5
]}

Marais, Richard ^{[2
]}

Sahai, Erik ^{[1
]}

机构：

[1] Canc Res UK London Res Inst, Tumor Cell Biol Lab, London WC2A 3LY, England

[2] Canc Res UK Manchester Inst, Mol Oncol Grp, Manchester M20 4BX, Lancs, England

[3] Canc Res UK London Res Inst, Expt Histopathol Lab, London WC2A 3LY, England

[4] Kyoto Univ, Grad Sch Biostudies, Lab Bioimaging & Cell Signalling, Kyoto 6068315, Japan

[5] Royal Marsden NHS Trust, Dept Med Oncol, London SW3 6JJ, England

来源：

CANCER CELL | 2015年 / 27卷 / 04期

基金：

英国惠康基金;

关键词：

CELL LUNG-CANCER; CHRONIC MYELOID-LEUKEMIA; RAF INHIBITORS; ACQUIRED-RESISTANCE; MUTANT MELANOMA; METASTATIC MELANOMA; KINASE INHIBITORS; TUMOR PROGRESSION; TYROSINE KINASE; EGFR;

D O I：

10.1016/j.ccell.2015.03.008

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

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 beta 1/FAK/Src signaling in melanoma cells. Fibronectin-richmatrices 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.

引用

页码：574 / 588

页数：15

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