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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-? (TGF-?) from the melanoma cells that increased the differentiation state of the fibroblasts, an affect associated with fibronectin deposition, increase in ?-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.

SUBMITTER: Fedorenko IV

PROVIDER: S-EPMC4648653 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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BRAF Inhibition Generates a Host-Tumor Niche that Mediates Therapeutic Escape.

Fedorenko Inna V IV Wargo Jennifer A JA Flaherty Keith T KT Messina Jane L JL Smalley Keiran S M KSM Smalley Keiran S M KSM

The Journal of investigative dermatology 20150824 12

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 thr ...[more]

PMID: 26302068

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Project description:BackgroundDespite the promise of dual BRAF/MEK inhibition as a therapy for BRAF-mutant (BRAF-mut) melanoma, heterogeneous responses have been observed in patients, thus predictors of benefit from therapy are needed. We have previously identified semaphorin 6A (SEMA6A) as a BRAF-mut-associated protein involved in actin cytoskeleton remodeling. The purpose of the present study is to dissect the role of SEMA6A in the biology of BRAF-mut melanoma, and to explore its predictive potential towards dual BRAF/MEK inhibition.MethodsSEMA6A expression was assessed by immunohistochemistry in melanoma cohort RECI1 (N = 112) and its prognostic potential was investigated in BRAF-mut melanoma patients from DFCI and TCGA datasets (N = 258). The molecular mechanisms regulated by SEMA6A to sustain tumor aggressiveness and targeted therapy resistance were investigated in vitro by using BRAF-mut and BRAF-wt melanoma cell lines, an inducible SEMA6A silencing cell model and a microenvironment-mimicking fibroblasts-coculturing model. Finally, SEMA6A prediction of benefit from dual BRAF/MEK inhibition was investigated in melanoma cohort RECI2 (N = 14).ResultsOur results indicate higher protein expression of SEMA6A in BRAF-mut compared with BRAF-wt melanoma patients and show that SEMA6A is a prognostic indicator in BRAF-mut melanoma from TCGA and DFCI patients cohorts. In BRAF-mut melanoma cells, SEMA6A coordinates actin cytoskeleton remodeling by the RhoA-dependent activation of YAP and dual BRAF/MEK inhibition by dabrafenib+trametinib induces SEMA6A/RhoA/YAP axis. In microenvironment-mimicking co-culture condition, fibroblasts confer to melanoma cells a proliferative stimulus and protect them from targeted therapies, whereas SEMA6A depletion rescues the efficacy of dual BRAF/MEK inhibition. Finally, in BRAF-mut melanoma patients treated with dabrafenib+trametinib, high SEMA6A predicts shorter recurrence-free interval.ConclusionsOverall, our results indicate that SEMA6A contributes to microenvironment-coordinated evasion of melanoma cells from dual BRAF/MEK inhibition and it might be a good candidate predictor of short-term benefit from dual BRAF/MEK inhibition.

Dataset Information

BRAF Inhibition Generates a Host-Tumor Niche that Mediates Therapeutic Escape.

Publications

BRAF Inhibition Generates a Host-Tumor Niche that Mediates Therapeutic Escape.

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