Scholarlink

<p>Resistance to anti-EGFR therapy remains a major challenge in head and neck squamous cell carcinoma (HNSCC), as adaptive mechanisms driven by drug-tolerant persister cells (DTPs) ultimately compromise treatment efficacy. Here, we identify Interleukin-1 (IL-1)-mediated inflammation as a critical driver of resistance to the anti-EGFR monoclonal antibody cetuximab (CTX). Through meta-analysis of HNSCC patient datasets stratified by lymph node status, together with in vitro studies using sensitive and CTX-resistant HNSCC cell lines and in vivo nude mouse models, we demonstrate that IL-1 in the tumor microenvironment reduces EGFR degradation, thereby promoting receptor stability and therapeutic escape. In sensitive cells, CTX suppresses the IL-1 pathway via direct transcriptional downregulation of IL-1α and IL-1β; however, this regulatory effect is lost in resistant cells, where a sustained IL-1-driven pro-inflammatory program enhances invadopodia formation, proliferation, and metastatic potential. Importantly, pharmacological inhibition of IL-1 in mice restored sensitivity to anti-EGFR therapy and prevented lung metastatic dissemination of resistant cells. These findings uncover an inflammatory axis underlying resistance and suggest that targeting IL-1 may improve EGFR-targeted therapies and limit metastatic spread in HNSCC.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

IL-1-mediated inflammation promotes metastatic dissemination and resistance to EGFR-targeted therapy

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月8日

查看全文
  • Federica Pagano,
  • Cinzia Girone,
  • Francesco Borrelli,
  • Donatella Romaniello,
  • Valerio Gelfo,
  • Daria Maria Filippini,
  • Alessandra Morselli,
  • Martina Mazzeschi,
  • Giulia Querzoli,
  • Francesca Ambrosi,
  • Carmen Miano,
  • Gabriele D’Uva,
  • Francesco Fazi,
  • Pradeep Chaluvally-Raghavan,
  • Michela Sgarzi,
  • Balazs Győrffy,
  • Andrea Ardizzoni,
  • Mattia Lauriola

摘要

Resistance to anti-EGFR therapy remains a major challenge in head and neck squamous cell carcinoma (HNSCC), as adaptive mechanisms driven by drug-tolerant persister cells (DTPs) ultimately compromise treatment efficacy. Here, we identify Interleukin-1 (IL-1)-mediated inflammation as a critical driver of resistance to the anti-EGFR monoclonal antibody cetuximab (CTX). Through meta-analysis of HNSCC patient datasets stratified by lymph node status, together with in vitro studies using sensitive and CTX-resistant HNSCC cell lines and in vivo nude mouse models, we demonstrate that IL-1 in the tumor microenvironment reduces EGFR degradation, thereby promoting receptor stability and therapeutic escape. In sensitive cells, CTX suppresses the IL-1 pathway via direct transcriptional downregulation of IL-1α and IL-1β; however, this regulatory effect is lost in resistant cells, where a sustained IL-1-driven pro-inflammatory program enhances invadopodia formation, proliferation, and metastatic potential. Importantly, pharmacological inhibition of IL-1 in mice restored sensitivity to anti-EGFR therapy and prevented lung metastatic dissemination of resistant cells. These findings uncover an inflammatory axis underlying resistance and suggest that targeting IL-1 may improve EGFR-targeted therapies and limit metastatic spread in HNSCC.