Pyrotinib sensitizes 5‑fluorouracil‑resistant HER2-positive breast cancer cells to 5‑fluorouracil

Abstract BACKGROUND: Clinical trials have shown that pyrotinib+ capecitabine significantly improved efficacy of patients with human epidermal growth factor receptor 2(HER2) +breast cancer. However, whether pyrotinib sensitizes 5‑Fluorouracil(5‑FU)‑resistant breast cancer cells to 5‑FU is unknown. This study aimed to investigate the effects of pyrotinib on HER2+breast cancer cells with resistance to 5‑FU and provide new clues for the pyrotinib treatment in 5-FU-resistant breast cancer.METHODS: the 5‑FU‑resistant breast cancer cell lines SK-BR-3/FU and MAD-MB-453/FU were established by continuous exposure of the parental cells to 5‑FU.The effects of pyrotinib on these cell lines were examined by growth inhibitory activity assay, reverse transcription‑quantitative polymerase chain reaction, Western blot analysis, high-performance liquid chromatography and animal experiments.RESULTS: Pyrotinib inhibited the proliferation of 5-FU-resistant and parental HER2-positive breast cancer cells and re-sensitized resistant cells to 5-FU by decreasing the expression of thymidylate synthase(TS) and ABC transporter subfamily G member 2(ABCG2). In a xenograft model, combination treatment with 5-FU and pyrotinib showed greater antitumor activity than either agent alone. CONCLUSIONS: Our results offer a preclinical rationale for clinical investigations of combination treatment with pyrotinib and 5-FU for 5-FU-resistant HER2-positive breast cancer.