NF-κB Regulation of c-FLIP Promotes TNFα-Mediated RAF Inhibitor Resistance in Melanoma

The Journal of Investigative Dermatology
Y ShaoA E Aplin

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-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.

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Citations

Oct 30, 2019·Apoptosis : an International Journal on Programmed Cell Death·Aleksandra Mielczarek-LewandowskaMalgorzata Czyz
Mar 9, 2017·Medical Science Monitor : International Medical Journal of Experimental and Clinical Research·Jichun SunXiaoxin Jin
Jun 9, 2018·Cell Death & Disease·Fu Xi LeiXu Dong Zhang
May 5, 2016·Journal of Molecular Signaling·Lihua Tang, Kepeng Wang
May 30, 2020·International Journal of Molecular Sciences·Mariusz L HartmanMalgorzata Czyz
Jan 7, 2021·Cellular & Molecular Biology Letters·Michal Tracz, Wojciech Bialek
Mar 17, 2021·European Journal of Pharmacology·Yan LiWeimin Deng
May 6, 2021·Cancers·Etienne Leveille, Nathalie A Johnson

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Methods Mentioned

BETA
xenograft
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flow cytometry

Software Mentioned

SAS
Flowjo

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