Repurposing Antimalarial Lumefantrine for Targeted Therapy in Triple-Negative Breast Cancer

Abstract

Triple-negative breast cancer (TNBC) remains the most aggressive subtype of breast cancer, characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. Due to the lack of these classical molecular targets, clinical management is heavily reliant on systemic chemotherapy, which suffers from severe off-target toxicities and a high incidence of chemoresistance. The drug repurposing paradigm offers an accelerated, economically viable framework to identify novel oncology indications for well-characterized, FDA-approved non-oncology therapeutics. Lumefantrine, a well-established antimalarial agent, has recently emerged as a promising candidate for oncological repositioning. Preclinical evidence indicates that lumefantrine targets the Friend leukemia integration 1 (Fli-1) transcription factor network, subsequently suppressing downstream effectors including heat shock protein B1 (HSPB1), matrix metalloproteinases (MMPs), and signaling cascades linked to epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) remodeling. Furthermore, lumefantrine acts synergistically with conventional chemotherapeutics to overcome drug resistance and inhibit cell proliferation. This review evaluates the mechanistic foundation, preclinical progress, therapeutic combinations, and formulation hurdles associated with repurposing lumefantrine as a targeted agent in TNBC management.

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