Towards the first targeted therapy for triple-negative breast cancer: Repositioning of clofazimine as a chemotherapy-compatible selective Wnt pathway inhibitor

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 wellcharacterized 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.

Mechanisms of Chemotherapy Resistance in Triple-Negative Breast Cancer—How We Can Rise to the Challenge

“…CWP232228, a small molecule that selectively inhibits Wnt pathway signaling by blocking nuclear β-catenin interaction with T-cell factor, reduced tumor growth in TNBC xenograft models and had a strong effect against chemoresistant breast CSC both in vitro and in vivo [84]. A repurposed drug clofazimine demonstrated efficacy in reducing the proliferation of TNBC cells and tumor growth in xenograft models [85]. Clofazimine negatively impacted β-catenin accumulation in the cytosol, thus downregulating the pathway and reducing the expression of ABC transporters [85].…”

Immunotherapy: A Challenge of Breast Cancer Treatment

“…Chemotherapy is the current standard of care for advanced TNBC despite limited efficacy and poor survival outcomes [13]. Different targeted treatments for TNBC are under pre-clinical or clinical development [13,14]. Even though most breast cancer patients are diagnosed early enough to be successfully treated with surgery, chemotherapy, radiotherapy, or a combination thereof [8], nearly 30% of women that are initially diagnosed with early-stage disease will eventually develop a metastatic disease [7], which ultimately leads to patient death.…”

Interplay Between Autophagy and Wnt/β-Catenin Signaling in Cancer: Therapeutic Potential Through Drug Repositioning

“…This drug inhibited Wnt/β-catenin signaling efficiently, suppressed growth tumor, and induced apoptosis. Moreover, the authors observed that clofazimine was compatible with doxorubicin and that this combination demonstrated an additive effect both in vitro and in vivo (47).…”