A novel kinase inhibitor, Regorafenib, blocks EGFR-dependent signaling to repress tumour metastasis in human triple-negative breast cancers.

INTRODUCTION: Triple-negative breast cancer (TNBC), the most aggressive subtype, poses a significant challenge as approved targeted therapies are lacking. The epidermal growth factor receptor (EGFR) is highly expressed in over 50% of TNBC cases and is implicated as a key driver in TNBC progression. Regorafenib, a small-molecule inhibitor of multiple receptor tyrosine kinases, is utilized as a second-line treatment for metastatic tumors. METHODS: Bioinformatics analysis and clinical analysis of 14 breast cancer cases revealed the EGFR expression and activation in tumor tissues. Functional validation through in vitro and in vivo models demonstrated EGFR's oncogenic role and Regorofenib's inhibitory effect. Mechanistically, multi-molecular biology methods and transcriptomics analysis identified EGFR-associated pathway driving TNBC lung metastasis. RESULTS: In this study, we demonstrate that Regorafenib, acting as an inhibitor of EGFR, exhibits potent anti-metastatic effects both in vitro in TNBC cell lines expressing EGFR and in vivo in mouse models of TNBC lung metastasis. Mechanistically, Regorafenib-mediated EGFR inhibition suppresses signaling in the Src-JNK/p38-YAP1 pathway, decreases STAT3 and NF-κB activation, thereby impeding epithelial-to-mesenchymal transition and metastasis. DISCUSSION: Our discovery of Regorafenib as a novel inhibitor of EGFR activation provides valuable insights for TNBC-specific anti-EGFR therapies targeting metastasis.