p38 inhibition restores chemosensitivity of tumor cells by disrupting oligomerized breast cancer resistance protein membrane trafficking.

Breast cancer resistance protein (ABCG2) significantly contributes to decreased sensitivity of tumor cells to chemotherapy. While ABCG2 inhibitors exist, multidrug resistance remains unresolved due to limited specificity, toxicity, and heterogeneous expression. To overcome this, we sought to identify key upstream regulators. We assessed drug sensitivity and identified ABCG2 as broadly overexpressed across tumor types and negatively correlated with chemosensitivity. Cell lines with higher ABCG2 expression exhibited lower sensitivity to mitoxantrone, topotecan, and doxorubicin and diminished cytotoxic response. Notably, p38 activation strongly correlated with ABCG2-mediated chemoresistance. Inhibiting p38 phosphorylation effectively downregulated ABCG2 expression and oligomerization. This suppression impaired the drug efflux function of ABCG2, significantly enhancing the cytotoxicity of the chemotherapeutics. Mechanistically, p38 regulated the expression and membrane localization of oligomeric ABCG2, essential for its efflux activity. This study highlights p38 as a promising target to overcome ABCG2-mediated multidrug resistance and improve treatment outcomes for drug-resistant tumors.