Abstract:
Hormonal therapy is necessary in hormone receptor-positive breast cancer patients. It is used in both early and advanced-stage patients. Unfortunately, many patients developed endocrine resistance later on after the treatment was initiated and this could progress the disease. Endocrine resistance results from many mechanisms, including HER2 signaling pathway. These resistant breast cancer cells exhibit more HER2 signaling proteins such as AKT and ERK, compared to wild-type hormone receptor-positive breast cancer cells. Palbociclib is a CDK4/6 inhibitor and is indicated in patients who developed tamoxifen resistance. Lapatinib is a dual tyrosine kinase inhibitor- HER1 and HER2 and is used in HER2-overexpressed breast cancer patients. Palbociclib combined with lapatinib was investigated in head and neck squamous cell carcinoma and this resulted in synergistic cytotoxic activity and a decrease in ERK1/2 phosphorylation. However, combining these two drugs has not been used in endocrine-resistant breast cancer cells whose tumors overexpressed HER2 after hormonal therapy. In this study, we investigated the combination effect of these two drugs in MCF-7/LCC2 and MCF-7/LCC9 breast cancer cells, including cytotoxic activity, anti-invasion, and the mechanism behind it. Lapatinib combined with palbociclib at IC50 showed a significantly increased cytotoxic activity. Moreover, the combination of these drugs resulted in higher anti-invasion activity than either single drug alone did. Lapatinib combined with palbociclib also significantly suppressed Epithelial-mesenchymal transition (EMT) markers such as Snail and pAKT more than either single drug alone did, which was also confirmed by the anti-invasion activity. Therefore, our research demonstrated that the combination of CDK4/6 inhibitor and anti-HER2 drugs showed promising results and could be further investigated in clinical trials.
