The TWEAK receptor Fn14 is a therapeutic target in melanoma: immunotoxins targeting Fn14 receptor for malignant melanoma treatment.

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The Journal of investigative dermatology, ISSN: 1523-1747, Vol: 133, Issue: 4, Page: 1052-62

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Zhou, Hong; Ekmekcioglu, Suhendan; Marks, John W; Mohamedali, Khalid A; Asrani, Kaushal; Phillips, Keeley K; Brown, Sharron A N; Cheng, Emily; Weiss, Michele B; Hittelman, Walter N; Tran, Nhan L; Yagita, Hideo; Winkles, Jeffrey A; Rosenblum, Michael G Show More Hide
Elsevier BV
Biochemistry, Genetics and Molecular Biology; Medicine; Animals; Cell Death; Cell Line; Tumor; Drug Design; Female; Humans; Immunologic Factors; Immunotoxins; Melanoma; Mice; Inbred BALB C; NF-kappa B; Protein Binding; Receptors; Tumor Necrosis Factor; Signal Transduction; Skin Neoplasms; Up-Regulation; Xenograft Model Antitumor Assays; Oncology
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Fibroblast growth factor-inducible protein 14 (Fn14), the cell surface receptor for tumor necrosis factor-like weak inducer of apoptosis (TWEAK), is overexpressed in various human solid tumor types and can be a negative prognostic indicator. We detected Fn14 expression in ∼60% of the melanoma cell lines we tested, including both B-Raf WT and B-Raf(V600E) lines. Tumor tissue microarray analysis indicated that Fn14 expression was low in normal skin, but elevated in 173/190 (92%) of primary melanoma specimens and in 86/150 (58%) of melanoma metastases tested. We generated both a chemical conjugate composed of the recombinant gelonin (rGel) toxin and the anti-Fn14 antibody ITEM-4 (designated ITEM4-rGel) and a humanized, dimeric single-chain antibody of ITEM-4 fused to rGel (designated hSGZ). Both ITEM4-rGel and hSGZ were highly cytotoxic to a panel of different melanoma cell lines. Mechanistic studies showed that both immunotoxins induced melanoma cell necrosis. In addition, these immunotoxins could upregulate the cellular expression of Fn14 and trigger cell-signaling events similar to the Fn14 ligand TWEAK. Finally, treatment of mice bearing human melanoma MDA-MB-435 xenografts with either ITEM4-rGel or hSGZ showed significant tumor growth inhibition compared with controls. We conclude that Fn14 is a therapeutic target in melanoma and the hSGZ construct appears to warrant further development as a therapeutic agent against Fn14-positive melanoma.