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Interleukin-1 blockade overcomes erlotinib resistance in head and neck squamous cell carcinoma

Aditya Stanam1,2, Katherine N Gibson-Corley2,3,4, Laurie Love-Homan2

  • 1Interdisciplinary Human Toxicology Program, The University of Iowa, Iowa City, IA, USA.

Oncotarget
|October 15, 2016
PubMed

Insights

Blocking interleukin-1 (IL-1) signaling with anakinra overcomes erlotinib resistance in head and neck squamous cell carcinoma (HNSCC) models. This approach may offer a new strategy for treating HNSCC patients resistant to EGFR inhibitors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Erlotinib shows limited efficacy in head and neck squamous cell carcinoma (HNSCC) due to rapid acquired resistance.
  • Understanding resistance mechanisms is crucial for developing effective HNSCC treatments.
  • Interleukin-1 (IL-1) signaling pathway alterations are implicated in cancer progression and drug resistance.

Purpose of the Study:

  • To investigate novel pathways contributing to erlotinib resistance in HNSCC.
  • To evaluate the therapeutic potential of blocking IL-1 signaling in overcoming erlotinib resistance.
  • To assess the impact of IL-1 blockade on tumor growth, vascularization, and patient survival.

Main Methods:

  • Comparative gene expression profiling of erlotinib-resistant (ER) versus erlotinib-sensitive (ES) HNSCC cell lines.
  • Analysis of interleukin-1 alpha (IL1A), interleukin-1 beta (IL1B), and IL-1 receptor antagonist (IL-1RA) expression and secretion.
  • In vivo studies using HNSCC xenografts treated with anakinra (IL-1 receptor antagonist) alone and in combination with erlotinib.

Main Results:

  • IL-1 signaling pathway was significantly upregulated in ER HNSCC cells, with increased IL1A and IL1B expression and reduced IL-1RA secretion.
  • Anakinra treatment inhibited the growth of ER HNSCC xenografts and reduced their vascularization, unlike in ES xenografts.
  • Combined anakinra and erlotinib treatment demonstrated superior efficacy in reducing tumor growth and circulating G-CSF and IL-1β levels.
  • Elevated IL1A or IL1RAP mRNA levels correlated with shorter survival in HNSCC patients.

Conclusions:

  • Blockade of the IL-1 pathway using anakinra effectively overcomes erlotinib resistance in HNSCC.
  • Anakinra demonstrates anti-tumor and anti-angiogenic effects in preclinical HNSCC models.
  • Targeting the IL-1 pathway represents a promising therapeutic strategy to enhance EGFR inhibitor efficacy in HNSCC treatment.
Keywords:
anakinraerlotinib resistancehead and neck squamous cell carcinomainterleukin-1interleukin-1 receptor antagonist

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