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

## TL;DR

This study shows that inhibiting p38 can reverse drug resistance in tumors by disrupting the activity of the ABCG2 protein, which helps cancer cells expel chemotherapy drugs.

## Contribution

The study identifies p38 as a novel upstream regulator of ABCG2 and demonstrates that inhibiting p38 can overcome ABCG2-mediated multidrug resistance.

## Key findings

- p38 inhibition reduces ABCG2 expression and oligomerization.
- Blocking p38 enhances chemotherapy effectiveness by impairing ABCG2's drug efflux function.
- p38 regulates ABCG2 membrane localization, crucial for its resistance activity.

## Abstract

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.

•p38 acts as an upstream regulator of ABCG2•p38 inhibition reverses ABCG2-mediated multidrug resistance•Inhibiting p38 disrupts oligomeric ABCG2 membrane localization and blocks its drug efflux function

p38 acts as an upstream regulator of ABCG2

p38 inhibition reverses ABCG2-mediated multidrug resistance

Inhibiting p38 disrupts oligomeric ABCG2 membrane localization and blocks its drug efflux function

Cancer; Molecular network; Protein