Abstract 3705: Targeting interleukin-1 to increase cetuximab efficacy in head and neck cancer

Abstract

Abstract Treatment for head and neck squamous cell carcinoma (HNSCC) patients includes the epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab. However, response to cetuximab is low and resistance remains a critical issue. Therefore, it is imperative to develop strategies to enhance tumor response to this drug. Inflammation plays an important role in tumor progression by increasing the release of cytokines that promote tumor cell survival. Our prior work has shown that a variety of pro-inflammatory cytokines involved in tumor survival are upregulated upon treatment with EGFR inhibitors in HNSCC cells, suggesting that poor tumor response to EGFR inhibitors may be due to increased tumor-associated inflammation. Our lab has shown that the increased proinflammatory tumor response due to EGFR inhibition may be activated by interleukin-1 (IL-1) signaling, suggesting that the IL-1 pathway may be an important target to enhance the efficacy of anti-EGFR therapy. Here we investigated the effect of IL-1 blockade on HNSCC tumor response to cetuximab treatment. We found that cetuximab induced IL-6 secretion from SQ20B HNSCC cells and knockdown of the adapter protein MyD88, which is essential for IL-1 signaling, suppressed IL-6 secretion at baseline and in response to cetuximab treatment. Similarly, knock down of the IL-1 receptor (IL-1R) decreased baseline and cetuximab-induced IL-6 secretion, although IL-1R knockdown did not improve response to cetuximab in SQ20B xenografts in vivo. We additionally blocked IL-1 signaling using a recombinant IL-1R antagonist (IL-1RA). IL-1RA pre-treatment reduced baseline and cetuximab-induced IL-6 secretion in vitro. Although IL-1RA did not significantly enhance SQ20B tumor response to cetuximab, IL-1RA as a single agent significantly suppressed tumor growth in female mice but not in male mice. Finally, treatment with a human-specific neutralizing IL-1 alpha (IL-1α) antibody (but not IL-1 beta (IL-1β)) reduced baseline and cetuximab-induced IL-6 secretion in vitro, and significantly increased SQ20B tumor response to cetuximab in vivo. Altogether we propose that targeting IL-1α specifically may be a viable strategy to improve HNSCC tumor response to cetuximab. Citation Format: Madelyn Espinosa-Cotton, Ayana J. McLaren, Adam T. Koch, Andrean L, Simons. Targeting interleukin-1 to increase cetuximab efficacy in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3705. doi:10.1158/1538-7445.AM2017-3705