# Amphiregulin and Epiregulin Confer Radioresistance in Esophageal Squamous Cell Carcinoma Through Oxidative Phosphorylation

## TL;DR

This study identifies a pathway involving Amphiregulin and Epiregulin that makes esophageal cancer resistant to radiation therapy, suggesting new treatment strategies.

## Contribution

The study reveals a novel mechanism of radioresistance in ESCC through the CEBPB/AREG/EREG axis and OXPHOS reprogramming.

## Key findings

- High AREG/EREG levels correlate with resistance to chemoradiotherapy and poor prognosis in ESCC.
- Inhibiting the CEBPB/AREG/EREG axis or OXPHOS improves radiation sensitivity in ESCC cells.
- OXPHOS activity is a key metabolic determinant of radiotherapy outcomes in ESCC.

## Abstract

Neoadjuvant chemoradiotherapy (nCRT) improves outcomes for locally advanced esophageal squamous cell carcinoma (ESCC) but exhibits variable efficacy due to heterogeneous radiosensitivity. In this study, metabolic profiling of 59 ESCC patients revealed significant alterations in tricarboxylic acid cycle (TCA) cycle intermediates in pathological complete responders (pCR) vs. non‐responders (non‐pCR) ESCC patients after nCRT. Functional experiments demonstrated that radioresistant ESCC cells (KYSE410R) exhibited elevated OXPHOS activity, which is reversed by targeting TCA cycle enzymes (CPI‐613 (Devimistat), fumarate hydratase‐IN‐1 (FH‐IN‐1), etc.) or Oxidative phosphorylation (OXPHOS) inhibitors (IACS‐010759, Rotenone, etc.). Irradiation‐induced CCAAT Enhancer Binding Protein Beta (CEBPB) upregulated AREG/EREG expression, activating the ERBB/mTOR pathway to promote OXPHOS flux. Knockdown of CEBPB/AREG/EREG disrupted OXPHOS and sensitized ESCC cells to radiation. Clinically, high Amphiregulin/Epiregulin (AREG/EREG) levels correlated with nCRT resistance and poor prognosis. Collectively, the CEBPB/AREG/EREG axis drives radioresistance by reprogramming OXPHOS, suggesting inhibition of this pathway or OXPHOS itself as a promising strategy to enhance ESCC therapeutic responses.

Oxidative phosphorylation (OXPHOS) activity serves as a critical metabolic determinant of radiotherapy outcomes in esophageal squamous cell carcinoma (ESCC). The CEBPB/AREG/EREG axis drives radioresistance in ESCC by reprogramming OXPHOS. AREG and EREG function as predictive biomarkers for nCRT response and prognosis of ESCC patients. Targeting ERBBs or OXPHOS enhances IR efficacy, providing novel treatment strategies for ESCC patients.