Abstract 1972: Targeting the IL-6 signaling pathway overcomes cetuximab resistance in head and neck squamous cell carcinoma
Authors: O'Keefe Rachel A. , Bhola Neil E. , Lee David S. , Johnson Daniel E. , Grandis Jennifer R. 
Published: August 2018

Abstract
Head and neck squamous cell carcinoma (HNSCC), the sixth most common cancer worldwide, has a five-year survival rate of 50%. The last few decades have seen only marginal improvements to the survival rate due to high rates of resistance to currently available treatments. The only oncogene-targeted agent that has been FDA approved for the treatment of HNSCC is cetuximab, a monoclonal antibody directed against the epidermal growth factor receptor (EGFR). The response rate for single-agent cetuximab is below 20%, and both intrinsic and acquired resistance to cetuximab remain major obstacles in the treatment of HNSCC. Identification and targeting of mediators that confer cetuximab resistance are needed to improve patient outcomes in HNSCC and in other cancers in which cetuximab is employed. To address this unmet need, we generated cetuximab-resistant variants of the human HNSCC cell lines PE/CA-PJ49 and FaDu. Because secretion of interleukin 6 (IL-6) has been proposed as a mechanism of cetuximab resistance in HNSCC, we assessed IL-6 levels in these models of acquired resistance. IL6 mRNA expression was increased in PE/CA-PJ49 and FaDu cells that have acquired resistance to cetuximab compared to the parental cells from which they were derived. In addition, cetuximab-resistant PE/CA-PJ49 variants exhibited increased levels of glycoprotein 130 (gp130), a molecule that oligomerizes with IL-6R alpha (IL-6Rα) to form the IL-6 receptor. Since IL-6 is known to promote tumor cell proliferation and survival, we hypothesized that cetuximab-resistant PE/CA-PJ49 and FaDu variants would be sensitive to inhibition of components of the IL-6 signaling pathway. To test this hypothesis, we treated PE/CA-PJ49 parental cells and cetuximab-resistant variants with cetuximab and/or inhibitors of the IL-6 pathway. Colony formation assays revealed that cetuximab-treated parental cells formed fewer colonies than vehicle-treated cells, while cetuximab treatment did not affect the ability of cetuximab-resistant PE/CA-PJ49 variants to form colonies. In contrast, siRNA-mediated knockdown of IL6 or IL6R (encoding IL-6Rα) markedly reduced the colony-forming ability of the cetuximab-resistant variants, but not parental cells. These results suggest that targeted inhibition of IL-6 signaling inhibits proliferation and/or survival in cetuximab-resistant PE/CA-PJ49 cells. Ongoing studies are testing our hypothesis using small-molecule and antibody-based inhibitors of the IL-6 pathway in our cell line models and in cetuximab-resistant patient-derived xenografts. By conducting these experiments, we aim to assess the therapeutic potential of targeting the IL-6 pathway in cetuximab-resistant HNSCC.
Citation Format: Rachel A. O'Keefe, Neil E. Bhola, David S. Lee, Daniel E. Johnson, Jennifer R. Grandis. Targeting the IL-6 signaling pathway overcomes cetuximab resistance in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1972.