Low-dose EGFR inhibition unlocks ferroptosis susceptibility to sensitize chemotherapy in EGFR-high triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a highly heterogeneous subtype with a poor prognosis and limited therapeutics, for which metastasis is a primary driver. In this study, we explore the function of EGFR in breast cancer progression and the mechanistic basis of EGFR-targeted therapies, focusing on kinase inhibitors and protein degraders. In a murine breast cancer model, EGFR knockout exhibited minimal impact on primary tumor growth but significantly suppressed metastasis, supporting the clinical association between high EGFR expression and poor prognosis. At high doses, EGFR degraders exert their antitumor effect through kinase inhibition, not degradation, whereas low-dose EGFR inhibition has limited anti-proliferative activity. Gene-drug interaction screening identified gemcitabine (GEM) and decitabine (DAC) as agents interacting with EGFR, a finding confirmed by the observed resistance to these drugs in TNBC cell lines with high EGFR expression. Both low-dose EGFR degraders and inhibitors chemosensitize cells to GEM/DAC in vitro, with the EGFR degrader plus GEM combination exhibiting an enhanced inhibitory effect in a lung colonization model. Mechanistically, both low-dose EGFR degraders and inhibitors elevate ROS levels and induce lipid peroxidation, thereby sensitizing cancer cells to GEM/DAC-triggered ferroptosis. In summary, this study demonstrates that low-dose EGFR targeting creates a susceptible state for ferroptosis in tumor cells and, consequently, defines a combination therapy strategy of EGFR-targeted agents with chemotherapy for TNBC. Our results provide a foundation for the clinical translation of low-dose EGFR-targeting strategies and their rational combination with other agents.