Trifluridine/tipiracil exhibits potent antitumor activity in triple-negative breast cancer by targeting SKP2 and inducing cell cycle arrest and apoptosis

Trifluridine/Tipiracil (TFTD) is an innovative oral medication comprising trifluridine and tipiracil. While TFTD has shown efficacy in metastatic colorectal cancer, its therapeutic potential in triple-negative breast cancer (TNBC) remains unexplored. TNBC is an aggressive breast cancer subtype with limited treatment options and poor prognosis, making the development of effective therapies a significant clinical challenge. As chemotherapy remains the primary treatment strategy for TNBC, this study aims to investigate the efficacy of TFTD against TNBC and to elucidate its underlying mechanisms, which may provide a novel and promising therapeutic strategy for this difficult-to-treat disease. This study investigated the cytotoxic effects of TFTD on TNBC cells using CCK8 assays to determine IC50 values and Annexin V/PI staining to assess apoptosis and cell cycle progression. RNA-seq analysis was performed to identify treatment-related pathways, with findings validated through RT-qPCR and Western blotting. In vivo xenograft models were used to evaluate the therapeutic efficacy of TFTD. TFTD exhibited significant cytotoxic effects against TNBC cells, with IC50 values of 2.237 μmol (MDA-MB-231) and 2.792 μmol (BT-549). It induced apoptosis, reduced cells in the S-phase, and inhibited TNBC cell migration and invasion. RNA-seq analysis revealed significant downregulation of SKP2 and upregulation of GADD45A, E2F2, NF2, and CCND1. In vivo, TFTD significantly suppressed tumor growth and SKP2 expression. TFTD-mediated cytotoxicity and its ability to inhibit tumor growth in TNBC highlight its potential as a novel therapeutic candidate for addressing unmet clinical needs in TNBC treatment.