Co-loaded lapatinib/PAB by ferritin nanoparticles eliminated ECM-detached cluster cells via modulating EGFR in triple-negative breast cancer

Abstract

Cancer stem cell (CSC) cluster of triple-negative breast cancer (TNBC) is suggested to be responsible for therapy resistance, metastatic process and cancer recurrence, yet the sensitivity of CSC clusters of TNBC to ferroptosis remains elusive in a great measure. Current research revealed that epidermal growth factor receptor (EGFR) reinforced CD44-mediated TNBC cell clustering, whether blockade of EGFR has synergistic effects on erastin-induced tumor inhibition of CSC clusters is still poorly understood. Here, we found that fraction of CD24^lowCD44^high cells and size of tumor spheres clearly decreased following EGFR inhibition in TNBC cells. Inhibition of EGFR promoted expression of LC3B-II via YAP/mTOR signaling pathway, indicating that EGFR-mediated autophagy which contributed to ferroptosis. In order to further verify the protective effects of EGFR on ferroptosis induced by small molecules in TNBC cells, pseudolaric acid B (PAB) which led to ferroptosis of malignant cells was selected. In our experiment, lapatinib and PAB cotreatment inhibited TNBC cells viability and restrained formation of tumor spheres, accompanied with a high level of intracellular ROS. To target delivery lapatinib and PAB to TNBC cells, lapatinib/PAB@Ferritin (L/P@Ferritin) nanoparticles were prepared; results of in vitro and in vivo showed a higher tumor suppression efficiency of L/P@Ferritin, highlighting that it might provide a new perspective for treatment of CSC clusters of TNBC.