NF-?B Regulation of c-FLIP Promotes TNF?-Mediated RAF Inhibitor Resistance in Melanoma.

ABSTRACT: Targeted inhibitors elicit heterogeneous clinical responses in genetically stratified groups of patients. Although most studies focus on tumor intrinsic properties, factors in the tumor microenvironment were recently found to modulate the response to inhibitors. Here, we show that in cutaneous BRAF V600E melanoma, the cytokine tumor necrosis factor-? (TNF?) blocks RAF inhibitor-induced apoptosis via activation of NF-?B. Several NF-?B-dependent factors are upregulated following TNF? and RAF inhibitor treatment. Of these factors, we show that death receptor inhibitor cellular caspase 8 (FLICE)-like inhibitory protein (c-FLIP) is required for TNF?-induced protection against RAF inhibitor. Overexpression of c-FLIP_S or c-FLIP_L isoform decreased RAF inhibitor-induced apoptosis in the absence of TNF?. Importantly, targeting NF-?B enhances response to RAF inhibitor in vitro and in vivo. Together, our results show mechanistic evidence for cytokine-mediated resistance to RAF inhibitor and provide a preclinical rationale for the strategy of cotargeting the RAF/MEK/ERK1/2 pathway and the TNF?/NF-?B axis to treat mutant BRAF melanomas.

SUBMITTER: Shao Y 

PROVIDER: S-EPMC4466037 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature