Abstract
Prolonged treatment of breast cancer with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) often results in acquired resistance and a narrow therapeutic index. One strategy to improve the therapeutic effects of EGFR TKIs is to combine them with drugs used for other clinical indications. Ethacrynic acid (EA) is an FDA approved drug that may have antitumor effects and may enhance the cytotoxicity of chemotherapeutic agents by binding to glutathione and inhibiting WNT signaling. While the α,β-unsaturated-keto structure of EA is similar to that of irreversible TKIs, the mechanism of action of EA when combined with irreversible EGFR TKIs in breast cancer remains unknown. We therefore investigated the combination of irreversible EGFR TKIs and EA. We found that irreversible EGFR TKIs and EA synergistically inhibit breast cancer both in vitro and in vivo. The combination of EGFR TKIs and EA induces necrosis and cell cycle arrest and represses WNT/β-catenin signaling as well as MAPK-ERK1/2 signaling. We conclude that EA synergistically enhances the antitumor effects of irreversible EGFR TKIs in breast cancer.
Highlights
Breast cancer is the most common cancer and the leading cause of cancer death among women worldwide, with about 1.7 million cases and 521,900 deaths in 2012
We found that irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and ethacrynic acid (EA) synergistically inhibit breast cancer both in vitro and in vivo
To investigate the toxicity of irreversible EGFR TKIS and ethacrynic acid (EA) on breast cells lines, MCF7, MDA-MB-321 and 4T1 cells were treated with afatinib, neratinib and EA at different concentrations for 24h
Summary
Breast cancer is the most common cancer and the leading cause of cancer death among women worldwide, with about 1.7 million cases and 521,900 deaths in 2012. The incidence of breast cancer is much higher in the developed world, mortality rates are higher in the developing world, possibly because of the lack of affordable treatment and reduced access to mammography screening and tumor-receptor testing. It is necessary to continue to improve the therapeutic efficiency of affordable medicine in breast cancer. Overexpression, mutation, or aberrant activity of these receptors contributes to the progression of breast cancer by activating intracellular signaling cascades, including the MAPK-ERK and PI3K/AKT pathways [3], [4]. HER2 is overexpressed in 15-20% of all breast cancers and is correlated with poor prognosis. Treatments specific to different morphological types of breast cancer and relevant targets of the EGFR family are emerging as promising options
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