Intravital imaging reveals how BRAF inhibition generates drug-tolerant microenvironments with high integrin β1/FAK Signaling

Eishu Hirata, Maria Romina Girotti, Amaya Viros, Steven Hooper, Bradley Spencer-Dene, Michiyuki Matsuda, James Larkin, Richard Marais, Erik Sahai

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    227 Scopus citations

    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 3-12kPa 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.

    Original languageEnglish (US)
    Pages (from-to)574-588
    Number of pages15
    JournalCancer cell
    Volume27
    Issue number4
    DOIs
    StatePublished - Apr 13 2015

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    ASJC Scopus subject areas

    • Oncology
    • Cell Biology
    • Cancer Research

    Cite this

    Hirata, E., Girotti, M. R., Viros, A., Hooper, S., Spencer-Dene, B., Matsuda, M., Larkin, J., Marais, R., & Sahai, E. (2015). Intravital imaging reveals how BRAF inhibition generates drug-tolerant microenvironments with high integrin β1/FAK Signaling. Cancer cell, 27(4), 574-588. https://doi.org/10.1016/j.ccell.2015.03.008