NF-κB Regulation of c-FLIP Promotes TNFα-Mediated RAF Inhibitor Resistance in Melanoma.
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-α (TNFα) blocks RAF inhibitor-induced apoptosis via activation of NF-κB. Several NF-κB-dependent factors are upregulated following TNFα 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 TNFα-induced protection against RAF inhibitor. Overexpression of c-FLIP_S or c-FLIP_L isoform decreased RAF inhibitor-induced apoptosis in the absence of TNFα. Importantly, targeting NF-κB 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 TNFα/NF-κB axis to treat mutant BRAF melanomas.
Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology, Xi'an, China; Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China.
Yongping
Y
Shao
Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Kaitlyn
K
Le
Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Hanyin
H
Cheng
Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA; Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA. Electronic address: Andrew.Aplin@Jefferson.edu.
Andrew E
AE
Aplin
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics*; D045744:Cell Line, Tumor / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D007211:Indoles / Q000494:pharmacology*; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000187:drug effects / Q000235:genetics*; D049488:Phosphatidylethanolamine Binding Protein / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D012680:Sensitivity and Specificity; D012878:Skin Neoplasms / Q000188:drug therapy / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506387:Cflar protein, mouse; D007211:Indoles; D016328:NF-kappa B; C528407:PLX 4720; D049488:Phosphatidylethanolamine Binding Protein; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf