Synergistic therapeutic effects of pertuzumab and pyrrolitinib in HER-2-positive breast cancer: modulation of the PI3K/AKT pathway.

OBJECTIVE: To investigate the underlying mechanism of pertuzumab combined with pyrrolitinib in the treatment of breast cancer. METHODS: Real-time PCR and Western blot (WB) were used to detect the expression of HER-2 in breast cancer cells (MCF-10A, BT-474 and SK-BR-3). Subsequently, BT-474 cells were treated with different concentrations of pertuzumab (0, 0.1, 0.5, 1, 5, 10 μg/mL), pyrrolizinib (0, 2, 4, 6, 8, 10 nMol/L) or a synergistic mixture of pertuzumab and pyrrolizinib. The cell viability, migration, invasion and programmed cell death were detected by CCK-8, cell colony formation, wound healing, transwell migration, TUNEL apoptosis assay and WB. KEGG pathway analysis was used to identify key pathways with HER-2 involvement. String database was used to analyze the relationship between HER-2 and PI3K/AKT signaling pathway related proteins. Subsequently, the effects of HER-2 knockdown on PI3K/AKT signaling pathway and cell function were investigated. RESULTS: Elevated HER-2 expression was observed in breast cancer tissues and cells. The combination of pertuzumab and pyrrolitinib effectively reduced HER-2 levels, inhibited cell viability, proliferation, migration and infiltration, and promoted apoptosis. Knockdown of HER-2 inhibited the viability, proliferation, migration and invasion, downregulated the expression of PI3K and AKT, and increased the apoptosis of BT-474 cells, with these effects restored by IGF-1. CONCLUSION: Pertuzumab and pyrrolizinib target HER-2 to downregulate the PI3K/AKT signaling pathway, thereby inhibiting breast cancer cells.