Epidermal growth factor receptor inhibition potentiates chemotherapeutics‐mediated sensitization of metastatic breast cancer stem cells

Abstract

Abstract Background Metastasis has been a cause of the poor prognosis and cancer relapse of triple‐negative breast cancer (TNBC) patients. The metastatic nature of TNBC is contributed by the breast cancer stem cells (CSCs) which have been implicated in tumorigenesis. Higher expression of epidermal growth factor receptor (EGFR) in breast CSCs has been used as a molecular target for breast cancer therapeutics. Thus, it necessitates the design and generation of efficacious EGFR inhibitors to target the downstream signaling associated with the cellular proliferation and tumorigenesis of breast cancer. Aim To generate efficacious EGFR inhibitors that can potentiate the chemotherapeutic‐mediated mitigation of breast cancer tumorigenesis. Methods and Results We identified small molecule EGFR inhibitors using molecular docking studies. In‐vitro screening of the compounds was undertaken to identify the cytotoxicity profile of the small‐molecule EGFR inhibitors followed by evaluation of the non‐cytotoxic compounds in modulating the doxorubicin‐induced migration, in‐vitro tumorigenesis potential, and their effect on the pro‐apoptotic genes' and protein markers' expression in TNBC cells. Compound 1e potentiated the doxorubicin‐mediated inhibitory effect on proliferation, migration, in‐vitro tumorigenesis capacity, and induction of apoptosis in MDA‐MB‐231 cells, and in the sorted CD24+‐breast cancer cells and CD24−/CD44+‐breast CSC populations. Orthotopic xenotransplantation of the breast CSCs‐induced tumors in C57BL/6J mice was significantly inhibited by the low dose of Doxorubicin in the presence of compound 1e as depicted by molecular and immunohistochemical analysis. Conclusion Thus, the study suggests that EGFR inhibition‐mediated sensitization of the aggressive and metastatic breast CSCs in TNBCs toward chemotherapeutics may reduce the relapse of the disease.

Keywords

• breast cancer
• chemosensitization
• EGFR
• EGFR inhibitors
• orthotopic xenotransplantation