Unraveling the potential of USP8 as a therapeutic target for overcoming c-Met-mediated resistance in breast cancer: A review

Therapeutic resistance remains a serious challenge in breast cancer, and abnormal c-mesenchymal epithelial transition factor (c-Met) receptor tyrosine kinase (RTK) activation contributes to therapeutic resistance in many. Ubiquitin-specific peptidase 8 (USP8) has emerged as a modulator of RTK stability through deubiquitination and endosomal trafficking, and preclinical studies show that inhibition of USP8 speeds up ubiquitin-dependent degradation of RTKs, including c-Met and EGFR, suppresses PI3K/Akt and MAPK signaling, and reverses resistance phenotypes. In this review, we summarize mechanistic evidence for USP8 regulation of c-Met and related RTKs, explore preclinical studies that assess inhibition of USP8 as a strategy to sensitize RTK-driven tumors, and highlight translational limitations such as drug selectivity, toxicity, dosing, pharmacodynamics biomarkers, and patient selection that must be addressed prior to a clinical trial in breast cancer. While the therapeutic targeting of USP8 is promising, direct validation in breast cancer models and the development of robust pharmacodynamic markers and inhibitors that are clinically graded remain crucial next phase.