The exosomal compartment protects epidermal growth factor receptor from small molecule inhibitors.

Epidermal growth factor receptor (EGFR) plays a significant role in promoting breast cancer progression. However, targeting EGFR as a single treatment only resulted in moderate efficacy to the disease. The underlying mechanism of low responsiveness to EGFR inhibition remains largely unclear. Tumor-secreted extracellular vesicles (EVs) play a crucial role in mediating intercellular communication between tumor and stromal cells in local microenvironment and distant metastatic niche. Extracellular vesicles mediate cell-to-cell transfer of lipids, nucleic acids, and proteins. Although numerous recent studies have demonstrated exchanges of extracellular vesicles between cancer cells and the recipient cells contribute to tumor proliferation, invasion, and metastasis, yet little is known how the exosomal compartment responds to targeted therapies and their role in promoting drug resistance. In the current study we used a triple-negative breast cancer model to show that EV-encapsulated EGFR is protected from targeted inhibitors of EGFR and can trigger signaling pathway in recipient cancer cells, promoting proliferation and migration ability in vitro. Taken together, our study suggested a novel mechanism of drug resistance entailing the EV compartment, such as exosomes, as a target shelter which when released can signal for tumor promotion in the recipient cancer cells.