Activation of MAPK/ERK signaling in tumor fibroblasts confers resistance to BRAF inhibitors.

  • Major finding: Activation of MAPK/ERK signaling in tumor fibroblasts confers resistance to BRAF inhibitors.

  • Concept: Matrix remodeling promotes PLX4720 tolerance via integrin β1–FAK–SRC signaling in melanoma cells.

  • Impact: Coinhibition of BRAF and FAK may have enhanced clinical benefit in BRAF-mutant melanoma.

Small-molecule inhibitors targeting oncogenic kinases provide an early clinical benefit in tumors with matching oncogenic mutations; however, resistance due to intrinsic or acquired mechanisms remains a challenge. Preexisting genetically resistant subclones are not a common feature of BRAF-mutant melanoma, suggesting that non–cell autonomous mechanisms in the tumor stroma may also support the tumor in the face of targeted therapy. To monitor the response of tumor cells to BRAF inhibition within the context of the tumor microenvironment, Hirata and colleagues analyzed syngeneic murine BRAF-mutant melanoma tumors expressing an ERK/MAPK biosensor. Longitudinal intravital imaging showed that melanoma cells sensitive to the BRAF inhibitor PLX4720 in vitro became resistant to BRAF inhibition in vivo due to rapid reactivation of ERK/MAPK signaling in tumor areas with high stromal density. Coculture of patient-derived melanoma-associated fibroblasts (MAF) with murine melanoma cells was sufficient to confer PLX4720 tolerance in vitro; this tolerance was attributed to PLX4720-induced paradoxical activation of ERK/MAPK signaling and enhanced matrix-remodeling activity in MAFs, which promoted integrin β1 reorganization, increased FAK–SRC signaling, and ERK/MAPK reactivation in melanoma cells. Consistent with this finding, modulation of matrix composition or stiffness decreased PLX4720 sensitivity in vitro, with optimal cell survival observed on fibronectin matrices with 3 or 12 kPa stiffness. In addition, residual human melanoma tumors displayed increased ERK/MAPK signaling and matrix remodeling post-PLX4720 treatment. Importantly, combinatorial inhibition of FAK and BRAF prevented ERK/MAPK reactivation, synergistically enhanced melanoma cell death in vitro, and significantly impaired BRAF-mutant tumor growth in models of incomplete response to PLX4720, including a patient-derived xenograft. Together, these data support a model in which reactivation of ERK/MAPK signaling within the tumor stroma enables the survival of BRAF-mutant melanoma cells in the presence of BRAF inhibition prior to the emergence of resistance and suggest that strategies targeting the tumor microenvironment may be therapeutically effective in this disease.

Hirata E, Girotti MR, Viros A, Hooper S, Spencer-Dene B, Matsuda M, et al. Intravital imaging reveals how BRAF inhibition generates drug-tolerant microenvironments with high integrin β1/FAK signaling. Cancer Cell 2015;27:574–88.

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