Towards the first targeted therapy for triple-negative breast cancer: Repositioning of clofazimine as a chemotherapy-compatible selective Wnt pathway inhibitor. (1st May 2019)

• Record Type: Journal Article
• Authors: Ahmed, Kamal; Koval, Alexey; Xu, Jiabin; Bodmer, Alexandre; Katanaev, Vladimir L.
• Is Part Of: Cancer letters. Volume 449(2019)
• Page Start: 45
• Page End: 55
• Publication Date: 2019-05-01
• Subjects: Triple-negative breast cancer -- Clofazimine -- Wnt signaling -- Targeted therapy -- Drug combination; TNBC triple-negative breast cancer -- PLA2 phospholipase A2 -- NSG NOD-SCID-gamma -- CDI coefficient of drug interaction; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2019.02.018
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Wnt signaling is overactivated in triple-negative breast cancer (TNBC) and several other cancers, and its suppression emerges as an effective anticancer treatment. However, no drugs targeting the Wnt pathway exist on the market nor in advanced clinical trials. Here we provide a comprehensive body of preclinical evidence that an anti-leprotic drug clofazimine is effective against TNBC. Clofazimine specifically inhibits canonical Wnt signaling in a panel of TNBC cells in vitro . In several mouse xenograft models of TNBC, clofazimine efficiently suppresses tumor growth, correlating with in vivo inhibition of the Wnt pathway in the tumors. Clofazimine is well compatible with doxorubicin, exerting additive effects on tumor growth suppression, producing no adverse effects. Its excellent and well-characterized pharmacokinetics profile, lack of serious adverse effects at moderate (yet therapeutically effective) doses, its combinability with cytotoxic therapeutics, and the novel mechanistic mode of action make clofazimine a prime candidate for the repositioning clinical trials. Our work may bring forward the anti-Wnt targeted therapy, desperately needed for thousands of patients currently lacking targeted treatments. Highlights: Clofazimine inhibits Wnt signaling in a broad range of TNBC subtypes in vitro . Clofazimine acts through induction of apoptosis and cell cycle arrest. TNBC tumor xenograft growth is suppressed by oral clofazimine. Markers of Wnt signaling are lost in the xenograft tumors treated by clofazimine. Clofazimine is compatible with the cytotoxic chemotherapy agent doxorubicin.