Targeting the MAPK/ERK signaling pathway: Mechanistic analysis of pexidartinib in overcoming adriamycin resistance in breast cancer.

BACKGROUND AND PURPOSE: Breast cancer severely threatens women's health, adriamycin (Doxorubicin), as the first-line chemotherapy drug for breast cancer, has a serious problem of drug resistance, which severely restricts the prognosis of patients. No effective therapies are available for drug-resistant breast cancer, urging the development of novel strategies to overcome drug resistance.

RESEARCH DESIGN AND

METHODS

This study integrated transcriptomics and explored the mechanism of pexidartinib against MCF-7/ADR tumors via in vitro and in vivo experiments including fluorescence staining, flow cytometry and Western blot.

KEY

RESULTS

The CSF1R inhibitor pexidartinib potently inhibited adriamycin-resistant MCF-7/ADR cells with a much lower IC50 than parental cells. MAPK pathway enrichment was identified in drug resistance. Pexidartinib exerted multi-target synergy: suppressing MAPK/ERK and PI3K/AKT/mTOR pathways, blocking P-gp drug efflux, inducing ferroptosis and apoptosis, and inhibiting proliferation, migration and invasion. It also restrained xenograft growth, regulated related proteins and promoted tumor necrosis in nude mice.

CONCLUSION AND IMPLICATIONS: exidartinib overcomes adriamycin resistance in breast cancer through multi-target effects, providing a basis for clinical trials.