Alpelisib Exhibits a Synergistic Effect with Pyrotinib and Reverses Acquired Pyrotinib Resistance in HER2+ Breast Cancer

Background: Human epidermal growth factor receptor 2 (HER2) plays a vital role in breast cancer progression in patients who overexpress HER2, thus promoting the rapid progress of targeted drugs development and therapy strategies advancement targeting this gene. Pyrotinib, approved in clinical by the Chinese State Drug Administration, is a novel pan-ErbB kinase inhibitor and exhibits better efficacy than lapatinib. Alpelisib is a selective PI3K p110α inhibitor approved for application in HR+, HER2-, PIK3CA mutated breast cancers. We assumed that combining pyrotinib with alpelisib worked better than single-drug treatment.Methods: We performed the drug combination assay to evaluate the combination index (CI) of pyrotinib and alpelisib in HER2+ breast cancer cell lines. Cell functional assays, RT-qPCR (Real Time-Quantitative Polymerase Chain Reaction) and western blotting were performed to elucidate the combined efficacy of two drugs and explore the underlying mechanism. Then we established the acquired pyrotinib resistant HER2+ breast cancer cell lines and evaluate the combined efficacy of two drugs in pyrotinib resistant cells and explore the potential mechanisms.Results: Our data exhibited that a combination of alpelisib and pyrotinib showed a synergistic effect in HER2+ breast cancer by enhancing cell proliferation and migration decrease, G0-G1 cell cycle arrest, and apoptosis rate increase. Additionally, alpelisib combined with pyrotinib showed a tremendous synergistic effect in acquired pyrotinib resistant cells.Conclusions: Our results provided the preclinical evidence that a combination of pyrotinib and alpelisib as an effective therapeutic strategy in treating HER2+ breast cancer, whether patients were sensitive or resistant to pyrotinib treatment.