title: BRAF Inhibition Generates a Host-Tumor Niche that Mediates Therapeutic Escape.
abstract: The current study defines a fibroblast-derived niche that facilitates the therapeutic escape of melanoma cells from BRAF inhibition. Vemurafenib treatment led to the release of transforming growth factor-β (TGF-β) from the melanoma cells that increased the differentiation state of the fibroblasts, an affect associated with fibronectin deposition, increase in α-smooth muscle actin expression, and the release of neuregulin (NRG). At the same time, vemurafenib directly activated the fibroblasts through paradoxical stimulation of the mitogen-activated protein kinase pathway, causing them to secrete hepatocyte growth factor (HGF). Treatment with the BRAF/MEK inhibitor combination reversed the release of HGF. Adhesion of melanoma cells to fibronectin was critical in amplifying the fibroblast-derived NRG- and HGF-mediated PI3K/AKT (phosphatidylinositol 3'-kinase/AKT) survival signaling in the melanoma cells following BRAF inhibition. In coculture studies, combination treatment with inhibitors of BRAF/MET/HER kinase was ineffective at reversing the fibroblast-mediated therapeutic escape from BRAF inhibition. Instead, it was noted that combined BRAF/PI3K inhibition overcame fibroblast-mediated drug resistance in vitro and was associated with enhanced antitumor effects in an in vivo xenograft model. Thus, we show that melanoma cells and fibroblasts remodel their microenvironment in response to BRAF inhibition and that these adaptations allow tumor cells to evade therapy through increased PI3K/AKT survival signaling.
authors: The Department of Tumor Biology, The Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
authors: Inna V
authors: IV
authors: Fedorenko
authors: Department of Surgery, MD Anderson Cancer Center, Houston, Texas, USA.
authors: Jennifer A
authors: JA
authors: Wargo
authors: Department of Medicine, Massachusetts General Hospital, Boston, Massachussetts, USA.
authors: Keith T
authors: KT
authors: Flaherty
authors: The Department of Cutaneous Oncology, The Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
authors: Jane L
authors: JL
authors: Messina
authors: The Department of Tumor Biology, The Moffitt Cancer Center and Research Institute, Tampa, Florida, USA; The Department of Cutaneous Oncology, The Moffitt Cancer Center and Research Institute, Tampa, Florida, USA. Electronic address: keiran.smalley@moffitt.org.
authors: Keiran S M
authors: KSM
authors: Smalley
mesh_terms: D045744:Cell Line, Tumor; D005353:Fibronectins / Q000032:analysis; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D013449:Sulfonamides / Q000627:therapeutic use; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D000077484:Vemurafenib
chemical_list: D005353:Fibronectins; D007211:Indoles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D013449:Sulfonamides; D016212:Transforming Growth Factor beta; D000077484:Vemurafenib