Why does EGFR-targeted therapy continue to fail in breast cancer? From mechanistic deciphering to novel intervention strategies.

Epidermal growth factor receptor (EGFR) is overexpressed in a subset of breast cancers, particularly in triple-negative breast cancer (TNBC) and endocrine-resistant patients, representing a potential therapeutic target. Although multiple EGFR inhibitors have been successfully developed and approved for non-small cell lung cancer, colorectal cancer, and other malignancies, these drugs have repeatedly failed in breast cancer treatment, with numerous clinical trials confirming their limited efficacy. The underlying cause lies in the development of drug resistance, which may arise from the activation of compensatory pathways or the abnormal stability of the EGFR protein itself, ultimately resulting in an insufficient therapeutic response. To overcome this clinical dilemma, this review discusses protein-targeted degradation technologies, such as PROTAC and LYTAC. These technologies directly induce EGFR protein degradation via the ubiquitin-proteasome or lysosomal pathways, offering a novel direction to circumvent resistance to traditional small-molecule inhibitors. Future research should focus on precision molecular subtyping to optimize patient selection, in-depth analysis of resistance mechanisms, and exploration of novel combination therapeutic strategies, thereby improving response rates, overcoming resistance challenges, and paving the way for the development of effective individualized treatment strategies for EGFR-overexpressing breast cancer.